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J Mol Evol (1988) 27:283-290 J o u r n a l o fM o l e c u l a r v o l u t io n~ Springer-VerlagNew York I n c 1988

T h e E v o l u t io n a r y T r a n s it io n f ro m R N t o D N i n E a r l y C e l l sA. Lazcano, ~ R. Guer rero ,2 L. Margulis, 3 and J. Or 6 4Departamento de Microbiologia, Escuela Nacional de Ciencias Biol6gicas, IPN,Apartado Postal 4-870, 06400 Mrxico, Distrito Federal, MrxicoDepartamento de Microbiologiay Genrtica, Facultad de Ciencias, Universidad Autonoma de Barcelona,Bellaterra (Barcelona),Spain3Department of Biology, Boston University, Boston, Massachusetts 02215, USA4 Department of Biochemicaland BiophysicalSciences, Universityof Houston, Houston, Texas 77004, USA

S u m m a r y . The evolution of genetic material canbe divided into at least three major phases: first,genomes of nucl eic acid-like molecules; secondly,genomes of RNA; and finally, double-stranded DNAgenomes such as those present in all contemporarycells. Using pro pertie s of nucleic acid molecules, weattempt to explain the evolutionar y transition fr omRNA alone as a cellular informational macromol-ecule prior to the evolution o f cell systems based ondouble-stranded DNA. The idea that ribonucleicacid-based cellular genomes preceded D NA is basedon the following: (1) protein synthesis can occur inthe absence of DNA but not of RNA; (2) RNAmolecules have some catalytic properties; (3) theubiquity of purine and pyridine nucIeotide coen-zymes as well as other similar ribonucleotide co-factors in metabolic pathways; and (4) the fact thatthe biosynthesis of deoxyrib onucleoti des alwaysproceeds via the enzymatic reduction of ribonu-cleotides.

The RNA prior to DNA hypothesis can befurther developed by understanding the selectivepressures that led to the biosynthesis ofdeoxy ribose ,thymine, and proofreadin g DNA polymerases. Tak-en together these observations suggest to us thatDNA was selected as an informational molecule incells to stabilize earlier RNA-protein replicatingsystems. These arguments include the facts that (1)the 2'-deoxy-cont aining phosphodi ester backbone ismore stable in aqueous conditi ons and in the pres-

Offprint requests to J. Orb

ence of transition metal ions (such a s Z n 2+ than itsribo-equivalents; (2) the absence o f proofreading ac-tivity in RN A polymerases leads to a higher rate ofmutation in RNA genomes relative to DNA; (3)informat ion in RN A degrades because of the ten-dency of cytosine to deamin ate to uracil and thelack of a correcting enzyme; and (4) UV irradiationproduces a larger numb er of photochemical changesin RN A molecules relative to double-stranded DNA.The absence of atmospher ic UV at tenuation duringthe early Earth envi ronm ent (Hadean and early Ar-chean) would have imposed an intense selectionpressure favoring duplex DNA over other geneticinform ation storage systems.

If RNA preceded DN A as a reservoir of cellulargenetic informat ion, then an RNA-replicating oligo-peptide must have been one of the earliest proto-enzymes from which RNA polymerase presumablyevolved. We conclude that R N A polymerases areamong the oldest classes of enzymes.K e y w o r d s : Primordia l genomes Double-stranded DNA -- Early Darwinian evolu tion -- Ear-ly Earth environment -- RNA versus DNA

I n t r o d u c t i o nAn intracellular genetic apparatus capable of ex-pressing and, upon reproduction, transmitting to theprogeny information capable of undergoing evolu-tionary change is essential to all contemporary cells

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284(Margulis 1981; Hartman et al. 1985). The originof this ubiquitous genetic apparatus is a major prob-lem in the study of the appearance of life during theHadean or Archean eons.The idea that RNA preceded DNA as geneticmaterial has been expressed independen tly by man yauthors (e.g., Oparin 1961; Rich 1962; Haldane1965; Woese 1967; Crick 1968; Orgel 1968; Rean-ney 1979; Or6 and Lazcano 1984; Darnell andDooli ttle 1986). However, recent exper iments onnonenzymatic template-directed polymerization ofactivated simple nucleo tide analogues (Schwartz andOrgel 1985) and the spontaneous oligomerizationof purine-containing deoxynucleoside diphosphates(Schwartz 1986) have been interpreted to suggestthat both RNA and DNA were preceded by simplenucleic acid-like polymers (Schwartz 1987). Impor-tant evidence argues against the possibility that RNwas the first genetic material (Joyce et al. 1987)including the observations (1) that prebiotic syn-thesis of ribose yields only minor amounts of thissugar, which is quite unstable on a geological timescale, and (2) that nonenzymatic template-directedpolymerization of one activated ribonucleotide en-anti omer is inhibi ted strongly by the presence of theother. Thus, RNA was probably preceded in cellgenome evolution by a polymer made of flexible,acyclic, probably prochiral nucleotide analogues ofprebiotic origin (Joyce et al. 1987). Thus, althoughthe nature of the polynucleotides used as carriers ofgenetic information in the earliest forms of life isnot known, we assume that the evolution of genetictemplates followed this schematic progression: sin-gle-stranded RNA -. single-stranded DNA -, du-plex DNA.

Several factors lead to the hypothesis that a nu-cleic acid-like genome made a transition to RNAgenomes, including (1) the presence of the 2'-OHalong polynucleotides; (2) the rigidity of the furanosering; and (3) the enhanced nucleophilicity of theRN A 2'(3') cisglycol (Joyce et al. 1987).This paper reviews the evidence for a secondtransition: from cell RNA genomes alone to double-stranded DNA in addition to RNA. Here we arguethat double-stranded DNA molecules appeared incells with RNA genomes as a consequence of selec-tion pressures favoring an enhanced stability of thegenetic information . We believe the origin and evo-lution of biosynthetic pathways leading to the re-duction of ribose to deoxyribose, the formation ofthymine, and the presence of DN A polymerases withproofreading activity occurred subsequent t o the or-igin of life; DNA-based genetic systems were se-lected for inside cells by Darwinian mechani sms tostabilize earlier systems based on RNA replication,protein catalysis, and double-layered lipid mem-branes.

R N P r io r t o D N

Early-replicating and catalytic cell systems based onRNA (devoid of DNA) as suggested by Crick (1968)and Orgel (1968) have been discussed extensivelyelsewhere (Lazcano 1986). The argument includes:1) Prote in biosynthesis can take place in the ab-sence of DNA b ut not of RNA (Spirin 1986).2) The existence of viroids (Diener 1982) andRNA viruses (Reanney 1982) indicates that repli-cation systems can use either single- or double-stranded polyribonucleotides to store genetic infor-mation.3) RNA molecules have catalytic properties thatinclude endonuclease (Kruger et al. 1982; Guerrier-Takada et al. 1983), RNA ligase (Zaug and Cech

1985), exonuclease, and RN A po lymer ase (Zaug andCech 1986) activities. [For review, see Pace andMarsh (1985).]4) A number of ribonucleotide cofactors (coen-zymes) containing purines, pyrimidines, pyridines,and other nitrogenous bases are ubiquitous and es-sential to primary metabolism in extant metabolicpathways (White 1976, 1982). Furthermore, severalof these coenzymes can be synthesized under pre-biotic conditions (Mar et al. 1987).5) The 2 '-OH group of ribose (absent of coursein deoxyribose) may be directly involved in a num-ber ofphosphor ylat ions (Hal mann et al. 1969; Ush-er 1977) and amino acid condensation reactions(White and Erickson 1981).6) The biosynthesis of deoxyribonucleotides al-ways proceeds via the enzymatic reduction of ri-bonucleotides (Sprengel and Foll mann 1981; Lam-mers and Follmann 1983).All these points support a biotic rather than aprebiotic origin of the D NA system.

L i fe w i t h o u t D N

If our analysis is correct, early RN A genomes nevercoded for a number of proteins invo lved in DNAreplication such as DNA polymerases and DNA pri-mase (Reanney 1982; Lazcano 1986). However,genes coding for RNA replicase and o ther protein srequired for RNA maintenance and replication, aswell as the accompanying nucleoside triphosphatemetabolism (ATP, GTP), must have been the sinequa non of autopoietic systems of RN A-p rot ei ncells (Margulis and Guerrero 1987). As in contem-porary prokaryotes, some kind of RNA polymerasewas involved in tRNA and rRNA synthesis. Rep-lication of the R NA genome and ribosome-mediat-ed translation of RNA into proteins must have oc-curred within a dynamic lipoprotein membrane.Membranes are the essential prerequisite to Dar-winian evolution. Furthermore, they are essential

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285t o R N A - b a s e d ( o r a n y ) l i f e f o r m s b e c a u s e t h e ym a i n t a i n a n i n te r n a l m i c r o e n v i r o n m e n t d i f f er e n -t i a t i n g a u t o p o i e t i c e n t i t i e s f r o m t h e i r e x t e r n a l m i -l ie u ( O r 6 a n d L a z c a n o 1 9 8 7 ). T h e p r e s e n c e o f l i p id i cm e m b r a n e s r a i se s , h o w e v e r , t h e q u e s t i o n o f t h e d y -n a m i c r e l a ti o n s h i p b e t w e e n t h e c o n t e n t s o f t h e c e lla n d t h e e x t e r n a l m i l i e u .D i f f e r e n t v i r a l ( K a m e r a n d A r g o s 1 9 8 4 ) a n d e u -b a c t e r i a l n u c l e i c a c i d p o l y m e r a s e s ( L a z c a n o e t a l .1 9 8 7 ) s h a r e a h i g h l y c o n s e r v e d 1 4 - r e s i d u e s e g m e n tt h a t c o n s i s t s o f a n A s p - -A s p p a i r f l a n k e d b y h y d r o -p h o b i c a m i n o a c i d r es i d u es . T h i s s e g m e n t m a y b et h e a c t i v e s i t e a n d / o r t h e n u c l e i c a c i d r e c o g n i t i o nr e gi o n o f t h e n u c l e i c ac i d p o l y m e r a s e s ( K a m e r a n dA r g o s 1 9 8 4 ). A s e q u e n c e r ic h i n h y d r o p h o b i c a m i n oa c i d s p r e c e d e s a n A s p r e s id u e ; t h e s e s e q u e n c e s m a yb e in v o l v e d i n A T P o r i n o rg a n i c p y r o p h o s p h a t eb i n d i n g . P r o t e i n s d i s p l a y i n g t h e s e f e a t u r e s i n c l u d ee u b a c t e ri a l A T P s y n t h e t a se s , y e a s t - s o l u b l e i n o r g a n -i c p y r o p h o s p h a t e s , a n d o t h e r e n z y m e s ( B a l tc h e f fs k ye t a l. 1 9 8 7 ) , su g g e s t i n g t h e p o s s i b i l i t y o f a c o m m o no ri gi n fo r a n e ar ly R N A - d e p e n d e n t R N A p o l y m e r -a s e a n d m e m b r a n e - a s s o c i a t e d p r o t e i n s ( L a z c a n o e ta l . 1987) .What Se lec t ion Pres s ures Led tot h e D e v e lo p m e n t o f D o u b l e S t ra n d e d D N Ab y R N A B a s e d A u t o p o i e ti c S y st e m s ?T h e e v o l u t i o n a r y tr a n si ti o n f r o m R N A a s g e n o m i cm a t e ri a l to R N A s u p p l e m e n t e d b y d o u b l e - s tr a n d e dD N A h a s n o t b e e n e x p l a i n e d i n d e t a il ( b u t s e e F e r ri sa n d U s h e r 1 9 8 3 ) . W e s u g g e s t t h a t t h e s e l e c t i o n p r e s -s u r es f o r h ig h h e r i ta b i l i ty l e d t o t h e s u p p l e m e n t a t i o no f R N A c e ll s b y D N A a n d r e s u l te d i n t h e f o ll o w in g :(1 ) g r e a t e r s t a b i l i t y (t h e 2 - d e o x y - c o n t a i n i n g p h o s -p h o d i e s t e r b a c k b o n e i s m o r e s t a b l e i n a q u e o u s c o n -d i t i o n s , a n d i n t h e p r e s e n c e o f t r a n s i t i o n m e t a l i o n ss u c h a s Z n 2 t h a n i t s r i b o - e q u i v a l e n t ) ; ( 2) r e p a i r( a b s en c e o f p r o o f r e a d i n g a c t i v i t y in R N A p o l y m e r -a s e s l e a d s t o h ig h e r m u t a t i o n a l r a t e in R N A g e -n o r n e s r e l a t i v e t o D N A ) ; ( 3 ) r e s i s t a n c e t o c h e m i c a ld e g r a d a t i o n ( i n f o r m a t i o n i n R N A d e g r a d e s b e c a u s eo f t h e t e n d e n c y o f c y t o s i n e to d e a m i n a t e t o u r a ci l;n o R N A - d e p e n d e n t e n z y m e e x is ts c a p a b le o f re -v e r s in g t h is d e a m i n a t i o n ) ; a n d ( 4) U V s e n s i t iv i t y( U V i r ra d i a t io n p r o d u c e s a la rg e r n u m b e r o f p h o -t o c h e m i ca l c h an g e s in R N A a s c o m p a r e d t o d o u b l e -s t ra n d e d D N A ) . T h e s e a r g u m e n t s a r e d e v e l o p e d b e -low .

Stabil i ty to Basic HydrolysisT h e 2 - d eo x y - c o n t a in i n g p h o s p h o d i e s t e r o f D N A ism u c h m o r e r e s i s ta n t t o b a s i c h y d r o l y s i s t h a n i s i tsr i b o - e q u i v a l e n t ( F e r r i s a n d U s h e r 1 9 8 3 ) . T h e h y -d r o l y si s o f R N A p r o c e e d s v i a t h e f o r m a t i o n o f i n -

t e r m e d i a t e c y c li c 2 , 3 p h o s p h o n u c l e o s i d e s . T h ep h o s p h o d i e s t e r b o n d s o f D N A ( th a t la c k t h e T - O Hg r o u p o f r i b o s e r e q u i r e d t o f o r m t h e i n t e r m e d i a t e )a r e m o r e s t a b le u n d e r b a s i c c o n d i t i o n s . S e v e r a l d i-v a l e n t i o n s c a t a ly z e t h e h y d r o l y s i s o f t h e s u g a r -p h o s p h a te b a c k b o n e o f R N A ( B u tz o w a nd E i c h h o rn1 9 6 5 ; E i c h h o r n e t a l. 1 9 7 1 ) . Z i n c a f f o r d s a m u c hm o r e r a p i d r e a c t i o n t h a n a n y o t h e r m e t a l i o n s t e s te d .T h e z i n c - i n d u c e d d e p o l y m e r i z a t i o n r e q u i r e s t h ep r e s e n c e o f t h e 2 - h y d r o x y l . [ D N A , i n g e n e ra l , i s n o tr e a d i l y d e g r a d e d b y m e t a l i o n s ( B u t z o w a n d E i c h -h o r n 1 9 7 1) .] F r o m a n e v o l u t i o n a r y p o i n t o f v i e wt h e s e r e s u l t s a re i m p o r t a n t . Z i n c i o n s , u s e d e f f ic i e n t-l y f o r t e m p l a t e - d i r e c t e d p o l y m e r i z a t i o n r e a c t io n s o fa c t i v a t e d n u c l e o t i d e s ( B r i d s o n e t a l . 1 9 8 1 ) , a r ek n o w n t o b e p r e s e n t i n t h e a c t iv e s i te o f m o s t D N Aa n d R N A p o l y m e r a s e s ( M i t d v a n a n d L o e b 1 9 79 ).I t is t h e r e f o r e e a s y to e n v i s i o n t h e r e t e n t i o n o f z i n c -c a t a l y z ed p o l y m e r i z a t i o n r e a c t io n s p r i o r t o a n d a f t e rt h e e v o l u t i o n o f t h e f ir st a u t o p o i e t i c s y s t e m s .Ex i s t e n c e o f D N Pr o o fr e a din g En z y m e sP h a g e s , b a c t e r i a , a n d m a n y e u k a r y o t e s e x h i b i t a tl e a s t s o m e m i n o r 3 -5 e x o n u c l e a s e a c t i v it y in t h e irD N A p o l y m e r a s e s , a ll o w i n g th e m t o ed i t n e w l y s y n -t h e s i z e d D N A . M i s m a t c h e d b a s e s a r e e x c i s e d a n dr e c o p i e d o n c e a m i s t a k e i s d e t e c t e d ( L o e b a n d K u n -k e l 1 9 8 2 ). D N A m e t h y l a t i o n a l s o a l lo w s fo r n e w l yf o r m e d s t r a n d s t o b e d is t i n g u i s h e d f r o m p a r e n t a lo n e s ( F e rs h t 1 9 8 3 ; F r i e d b e r g 1 9 8 5) . R N A p o l y -m e r a s e s a r e n o t k n o w n t o p o s s e s s 3 - 5 e x o n u c l e a s ea c t iv i t y ; e v i d e n c e o f e r ro r - s u p p r e s s in g p r o o f r e a d i n gm e c h a n i s m s i n R N A h a s n o t b e en r e p o r te d ( R e a n -n e y 1 9 8 2 ; F e r s h t 1 9 8 3 ) . R N A r e p l i c a t i o n t h e r e f o r ei s i n t r i n s ic a l l y l e s s a c c u r a t e t h a n D N A r e p l i c a t i o n(Table 1) .T h e o ri gi n o f t h e e d it in g p r o p e r ti e s o f D N A p o l y -m e r a s e s c a n o n l y b e s u r m i s e d . T h e y p r o b a b l y s u c -c e e d e d t h e p o l y m e r i z i n g a c t i v i t y o f t h e s e e n z y m e s .C e l ls ca p a b l e o f u s i ng d o u b l e - s t r a n d e d D N A m o l -e c u l es w o u l d h a v e b e e n r a p i d l y s e l e c te d f o r. T h e s el a te r d e v e l o p e d p r o o f re a d i n g D N A p o l y m e r a s e s . T h el a c k o f 3 - 5 e x o n u c l e a s e a c t i v i ty in a l l R N A p o l y -m e r a s e s im p l i es t h a t R N A g e n o m e s c a n n o t a c h i e v ev e r y l a r g e s i z e s w i t h o u t r i s k i n g t h e i r g e n e t i c i d e n -t it ie s . T h e n u m b e r o f m i s p l a c e d n u c l e o t i d e s i s p r o -p o r t io n a l t o t h e l en g th o f t h e p r o d u c e d R N A ( R e a n -h e y 1 9 8 2) , a n e f fe c t t h a t c a n b e o b s e r v e d b y t h e h i g hn u m b e r o f m u t a t i o n s i n R N A v i r u se s (H o l l a n d e ta l . 1 9 8 2 ; R e a n n e y 1 9 8 2 ; S t e i n h a u e r a n d H o l l a n d1 9 8 7 ) . T h e s e g m e n t e d g e n o m e s f o u n d a m o n g c e r -t a i n R N A v i r u s e s m a y r e p r e s e n t a n e v o l u t i o n a r ys t ra t e g y t h a t o v e r c o m e s t h e i n a c c u r a c y o f R N Ap o l y m e r a s e s (R e a n n e y 1 9 8 2) . D u r i n g t h e e ar l y e v o -l u t i o n o f li fe , s e le c t iv e p r e s s u r es p r o b a b l y f a v o r e dD N A s u p p l e m e n t s a s re p o s i t o r ie s o f g e n e t ic i n f o r-

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2 8 6a b l e 1 . F i d e l i t y i n r e p l i c a t i o n

T e m p l a t e C a t a l y s t E r r o r - r a t e R e f e r e n c e s bP o l y ( C ) Z n 2+ a n d a c t i v a t e d n u c l e o t i d e s 1 0 - ~ - 1 0 - 2 1 , 2R N A R N A r e p l i c a se s 1 0 - 3 - 1 0 -4 3 , 4S i n g l e - s t r a n d D N A f r o m p h a g e q~X 17 4 D N A p o l y m e r a s e E. coh) ~ 5 10 -7 5N o t e : o v e r a l l a c c u r a c y a c h i e v e d b y p r o k a r y o t e s w h e n c o p y i n g is i 0 - 7 - 1 0 - ~ m u t r a t i o n s p e r b a s e t r a n s c r i b e d ( L o e b a n d L o e b 1 9 8 2 )

E r r o r p e r b a s e t r a n s c r i b e d .R e f e r e n c e s: ( 1 ) B r i d s o n e t a l . 1 9 8 1 ; (2 ) O r g ei a n d L o h r m a n n 1 9 7 4; ( 3 ) E i g e n a n d S c h u s t e r 1 9 7 7 ; ( 4 ) S p r i n g g a t e a n d L o e b 1 9 7 5 ; (5 )F e r s h t 1 9 7 9

mation. The character of earlier RNA genomes musthave limited strongly not only the fidelity of hered-itary transmission of genetic information but thequan tity o f genetic content as well.

The S tab i l it y o f Ni trogen B asesDouble-stranded DNA is more stable to depuri-

nation by at least a factor of 10, and this may havebeen important for the accumulation of DN A (Mil-ler and Orgel 1974, p. 126). Hyd rol yti c react ions(deamination, depurination, and depyrimidation)are one to tw o orders of magnitud e higher in single-stranded DN A prepared from rat liver cells than indouble-stranded DNA from the same source (Singerand Kusmierek 1982). Similar detailed measure-ments for RNA molecules have not been made.However , assuming early RNA gen omes had single-stranded regions, it can be concluded that their hy-drolytic lability would have been higher than tha tof their 2'-deoxy-equivalents (Ferris and Usher1983).

Deamina tion of cytosine into uracil in both RN Aand D NA under physiological condit ions is consid-erably faster than the other deaminat ion reactionssuffered by purine and pyrimidine bases (Singerand Ku smie rek 1982). As a consequence of thisdeamination the information in RNA tends to de-grade. Both the replacement of uracil with thyminein DNA and the removal of uracil from D N bythe correcting enzyme uracil-DNA glycosylase(Kornberg 1980) greatly enhanc e the stability of in-formati on storage in DNA relative to RNA. Clearly,uracil in DNA is not lethal; bacterial mutants areknown to persist through several generations withlevels of uracil in their DNA as high as one per 100of thymin e (Tye et al. 1978a) and Escherichia colimay remai n functional with as much as 30% of itsthymine replaced by uracil (cf. Kornberg 1980).Nevertheless, at least two enzymes have evolvedthat prevent the permane nt incorporation of uracilinto DNA.

One, dUTPas e, is a hydrolyt ic enzyme capableof converting dUT P into dUM P. This enzymemaintains low levels of the endogenous dUTP pool

and simultaneously provides the dUM P substratefor thymid ylat e synthetase (Kornberg 1980). T herole of dUTPase in the biosynthesis of dTTP sug-gests that dUTPase originated to prevent the mis-info rmat ion of uracil into D NA (Bertani et al. 1963).

The second mechanism, uraci l-DNA glycosylase,detects uracil (incorporated in place of thymi ne orderived from the hydrolysis of cytosine) and re-moves it by hydrolytic cleavage o f the uracil-sugarbonds. This e nzyme is present in considerable quan-tities in both eubacteria and eukaryotes (Kornberg1980; Lindahl 1982). Free uracil and pyrimidine-free DNA are products o f these reactions. The miss-ing pyridimines are usually quickly replaced; nu-cleotide excision-repair by DN A polymerase followsendonucleo lytic incision (Kornberg 1980).Deamination of cytosine to uracil is common bothin vivo and in vitro (Olivera 1978; Shlomai andKornberg 1978; Tye et al. 1978b). The ubiquity ofuracil-DNA glycosylase is an evolutionary adap-tati on that insured genetic stability (Kornberg 1980).Uracil-DNA glycosylase is highly conserved (Lin-dalai 1982) and mus t have evolve d after the devel-opment of the thymi ne biosynthetic pathway, i.e.,after the appearance o f dUTPase. Understandably,an equivalent system never developed among ceilsthat used RN A as informationa l polymers; becauseuracil is a natural constituent of RNA, any hypo-thetical uracil-RNA glycosylase system would beunable to distinguish between the uracil moleculesoriginally present in RNA, from those resulting fromdeamination of cytosine residues.S tab i l it y to Pho tochemica l D egrada tionThe flux of solar UV radiat ion at the surface of theearly Earth must have been higher than the contem-porary level. The lack of substantial amou nts o f freeatmospheric oxygen and the consequent lack of anoz one shield would account for the greater UV fluxof the Hadean and early Archean (Lazcano et al.1983; Schopf 1983). Moreover, calculations basedon satellite observations of young T-Ta uri stars re-sembling the young sun (Cant6 and Men doza 1983)suggest that young solar-like stars emit up to 104

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t i m e s m o r e u l t r a v i o l e t l i g h t t h a n t h e p r e s e n t s o l a rv a l u e G a u s t a d a n d V o g e l 1 9 8 2 ; C a n u t o e t a l. 1 9 8 2 ,1983) .

A m p l e p a l e o n t o l o g i c a l e v i d e n c e d o c u m e n t s t h ea p p e a r a n c e o f li fe b y t h e e a r ly A r c h e a n , m o r e t h a n3 . 5 x 1 09 y e a r s a g o K n o l l a n d B a r g h o o r n 1 9 7 7 ;A w r a m i k e t a l. 1 9 8 3 ; S c h o p f 1 9 8 3 ; S c h o p f a n dP a c k e r 1 9 8 7 ). S u ch h ig h l ev e l s o f u n a t t e n u a t e d U Vr a d i a t i o n l e d t o t h e e a r l y d e v e l o p m e n t a m o n g p r o -k a r y o t e s o f U V p r o te c t i o n m e c h a n i s m s M a r g u l i s e ta l. 1 9 7 6 ; M a r g u l i s 1 9 8 1 ). H i g h l y s o p h i s t i c a t e d e n -z y m e - m e d i a t e d D N A r e p a i r m e c h a n i s m s i n c l u d i n gp h o t o r e a c t i v a t i o n , w h i c h a r e f o u n d e v e n a m o n g o b -l i ga t e a na e r ob i c v i s ib l e l i gh t - i nse ns i t i ve ba c t e r i a l i kelostridium sporogenes R a m b l e r a n d M a r g u l i s1 9 8 0 ), a t t e st t o a n e a r l y a p p e a r a n c e o f m e c h a n i s m sp r o t e c t i n g D N A a g a i n s t p o t e n t i a l l y l e t h a l s o l a r r a -d i a t i o n .

U l t r a v i o l e t l i g h t c a u s e s m a j o r p h o t o c h e m i c a lc h a n g e s i n n u c l e i c a c i d s . A l t h o u g h t h e s u g a r s a n dp h o s p h a te g r o u ps o f b o t h D N A a n d R N A m a k ei n s i g n if i c an t c o n t r i b u t i o n s t o t h e a b s o r p t i o n s p e c t r aa t w a v e l e n g t h s g r e a t er t h a n 2 0 0 n m C a n t o r a n dS c h i m m e l 1 9 8 0) , t h e p u r i n e a n d p y r i m i d i n e m o i -e t ie s o f b o t h R N A a n d D N A s h o w v e r y s tr o n g a b -s o r p t i o n S h u g a r t 9 6 0 ) . W i t h t h e e x c e p t i o n o f u r i-d i n e , w h i c h a b s o r b s in t h e n e a r - U V a t 2 6 0 n m r a t h e rt h a n a t t h e 2 6 8 - n m p e a k o f t h y m i d i n e , t h e st a n d a rdd e o x y r i b o n u c l e o t i d e s a b s o r b a t e s s en t i al ly t h e s a m es p e c tr a a s t h e ir co r r e s p o n d i n g r ib o - c o m p o u n d s V o e te t al . 19 63) .

T h e t w o m o s t i m p o r t a n t t y p e s o f p h o t o p r o d u c t so f U V i r r a d i a t i o n o f n u c l e i c a c i d s a re 1 ) a c y c l o -b u t a n e r in g j o i n i n g t w o s e ts o f 5, 6 d o u b l e b o n d s o fa d j a c e n t p y r i m i d i n e r e si d u e s , a n d 2 ) p y r i m i d i n eh y d r a t e s F r i e d b e r g 1 98 5 ). U V - i r r a d i a t i o n s t u d i e so f t h e R N A p h a g e R 1 7 r e v e a l th a t t h e m a j o r p h o -t o c h e m i c a l p r o d u c t is u r a ci l h y d r a t e R e m s e n a n dC e r u t ti 1 9 7 2) . O f th e o t h e r p h o t o c h e m i c a l l e s io n sw h i c h i n c l u d e n u c l e i c a c i d - p r o t e i n l i n k s , b r e a k s i nt h e p h o s p h o d i e s t e r b a c k b o n e , a n d t h e f o rm a t i o n o f

c r o s s - l i n k s i n d o u b l e - s t r a n d e d D N A ) , t h e o n l y r e -v e r s i b le l e s io n i s th e f o r m a t i o n o f p y r i m i d i n e d i -m e r s S e t l o w 19 6 8 ; F r i e d b e r g 1 9 8 5 ) .T h e e x t e n t o f t h e U V - i n d u c e d p h o t o c h e m i c a lc h a n g e s i n n u c le i c a c id s d e p e n d s , a m o n g o t h e r t h i n g s ,o n t h e c o n f o r m a t i o n o f t h e m o l e c u l e ; s in g le - a n dd o u b l e - s t ra n d e d D N A m o l e c u l es p r e p a re d f r o m ~ X1 7 4 h a v e v e r y d i ff e r e n t U V s e n s i t i v i ti e s C e r u t t i e ta l. 1 9 65 ). T h e q u a n t i t y o f U V - i n d u c e d t h y m i n e d i -m e r i z a t i on i s s i gn i f i c a n t ly h ighe r i n t he s i ng l e -s t r a n d e d D N A f r o m Enterococcus M c L a r e n a n dS h u g a r 1 9 6 4 ) . W h e n p o l y r i b o n u c l e o t i d e s a r e U V -i rr a d ia t ed , t h e U V - i n d u c e d h y d r a t i o n o f p y r i m i d i n e si s s i g n i f i c a n t l y s u p p r e s s e d i n d o u b l e - s t r a n d e d r e l a -t i v e t o s i n g l e - s t r a n d e d m o l e c u l e s S e t l o w 1 9 6 8 ) . T h ef o r m a t i o n o f u r id i n e d i m e r s i s fi v e t i m e s g r e a te r

287i n p o l y U ) a s c o m p a r e d w i t h p o l y A ) : p o l y U ) c o -p o l y m e r s . T h e h y d r a t i o n o f u r i d y l i c a c id in p o l y A ) :p o l y U ) d u p l e x i s 1 0 t im e s l e s s t h a n i n p o l y U ) p o l y -m e r s P e a r s o n a n d J o h n s 1 9 6 6 ).T h e g e n o m e s o f e ar ly c e ll s, b e f o r e th e a p p e a r a n c eo f D N A , a r e t h o u g h t t o h a v e b e e n R N A m o l e c u le s .P r e s u m a b l y , t h e e a r l y c e l l u l a r R N A g e n o m e s c o n -t a i n e d s m a l l re g i o n s o f s h o r t c o m p l e m e n t a r y b a s e -p a i r i n g d o u b l e s t r a n d s , r e s u l t i n g f r o m r a n d o mm a t c h i n g p r o c e s s e s , a n d p r o b a b l y h a d l o n g s i n g l e -s t r a n d e d r e g io n s e x p o s e d t o p h o t o c h e m i c a l l e s i o n -i n g . U n d e r i n v i t r o c o n d i t i o n s , c o n t e m p o r a r y r e p -l i c at i o n o f s in g l e - s tr a n d e d p o l y n u c l e o t i d e s [ p o lyA ,C ) ] b y eu b a c t er i al D N A - d e p e n d e n t R N A p o l y -m e r a s e s i s r e p o r t e d l y m o r e e f fi c ie n t t h a n r e p l i c a t i o no f R N A m o l e c u l e s w i t h d o u b l e - s t r a n d e d r e g i on sL l a ca e t a l. 1 9 8 7) . In s u m m a r y , t h e a b s e n c e o f U Va t t e n u a t i o n d u r i n g t h e e a rl y E a r t h i m p o s e d a n i n -t e n s e s el e c ti o n p r e s s u re f a v o r i n g d u p l e x D N A m o l -

e c u l e s o v e r o t h e r p o s s i b l e g e n et i c i n f o r m a t i o n s t o r-a g e s y s t e m s .I n U V - i r r a d i a te d p o l y U ) u s e d a s m e s s e n g e r R N AG r o s s m a n 1 9 6 3 ) a n d a s a t e m p l a t e f o r i n v i t r o r e p -l i ca t io n A d m a n a n d G r o s s m a n 1 9 6 5) , u r a ci l h y -

d r a t e t e n d s t o c o d e a s c y t o s i n e ; c y t o s i n e h y d r a t ef o r m e d a f t e r U V i r r a d ia t i o n o f p o ly C ) c o d e s a su r a c i l W a c k e r e t a l. 1 9 6 4 ; O n o e t a l . 1 9 6 5 ; A d m a na n d G r o s s m a n 1 9 6 7) . T h e s e r e s u l ts c a n b e i n t er -p r e t e d a s e q u i v a l e n t t o t h e c h a n g e s i n s p e c i fi c it y o fb a s e - p a i r i n g d u e t o k e t o - e n o l a n d a m i n o - i m i n ot a u t o m e r i c s h i f t s i n u r a c il a n d c y t o s i n e , r e s p e c t i v e l yL a z c a n o 1 9 8 6) . U n d e r p h y s i o l o g i c a l c o n d i t i o n s ,h o w e v e r , t h e e n o l a n d i m i n o f o r m s a r e p r e s e n t i no n l y a b o u t o n e i n 1 0 - 4 - 1 0 - 5 S a e n g e r 1 9 8 4 ) , a n dm i s t a k e s a r e r ap i d l y c o rr e c t ed b y p r o o f r e a d i n g D N A

p o l y m e r a se s . In a D N A - d e p e n d e n t p o l y m e r a s e s y s-t e m , t h e p h o t o c h e m i c a l a l t e ra t io n o f R N A m o l e -c u l e s i n d u c e d b y U V i r ra d i a t io n w o u l d b e o f l it tl es ign i f ic a nc e Se t l ow 1968) . Ye t , e a r ly c e l ls w i th R N Ag e n o m e s w o u l d h a v e s u s t a i n e d v e r y h ig h r a te s o fU V - i n d u c e d m u t a t i o n s t h a t w e r e i r re p a r a b l e a n dw o u l d h a v e l o w h e r it a b il i ty . B e c a u s e D N A - r e p a i rs y s t e m s w o r k b y d u p l i c a t i o n o f t h e g e n e ti c in f o r -m a t i o n c o n t a i n ed i n th e c o m p l e m e n t a r y s t r an d s o ft h e d u p l e x D N A m o l e c u l e K o r n b e r g 1 9 8 0; F r i e d -b e r g 1 9 8 5 ), t h e e m e r g e n c e o f d o u b l e - s t r a n d e d D N Aw o u l d h a v e s t a b i l i z e d t h e e a r l i e r i r r e p a r a b l e R N As y s t e m s l e a d in g t o t h e s e l ec t io n o f m e c h a n i s m s t oc o r r e c t t h e d a m a g e c a u s e d b y U V l i g h t a n d , e v e n -t u a l ly , t o b a c t e r i a l s e x M a r g u l i s a n d S a g a n 1 9 8 6 ) .

o n c l u s i o n s

I n t h i s p a p e r w e h a v e a r g u e d t h a t t h e o r i g i n a n de v o l u t i o n o f t h e b i o s y n t h e t i c p a t h w a y s l e a d in g t ot h e r e d u c t i o n o f r i b o s e t o d e o x y r i b o s e , t h e a p p e a r -

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288ance of thymine, and the presence of DNA poly-merases with proofreading activity were not the re-sult of prebiotic processes; rather we claim thatDarwinian selective mechanisms, acting on RNAbased cells, led to DNA systems subsequent to theorigin of the cells themselves. Doub le-str anded RN Amolecules are very stable and do not separate easily.Thus, it is likely that single-stranded RNA cellulargenomes with some regions of short compl ement arybase-pairing double-stranded regions were followedduring early cellular evolution by single-strandedDNA genomes, and then by double-s tranded DNAgenomes. In su mmary, DNA- based genetic systemswould have stabilized earlier systems based on RN Areplication, themselves d escended f rom cells with anucleic acid-like ge nom e (Joyce et al. 1987). If weare correct, researchers carrying out experimentalefforts to achieve autopoiesy (Margulis and Sagan1986; Varela and Ma tur ana 1974) in the laborato ryought not to expect the formation ofprebiotic, i.e.,nonenzym atic, synthesis of a double-helix DN A ora DNA polymerase any more than they should ex-pect to achieve other complex semes that evolvedwithin living organisms, such as, for example, pho-tosensit ive ATP phosphorylation, excitable mem-branes, oxyge nic phot osynt hesis , or nucleated cells.We do not imply that deoxyribose and thymine wereabsent in the prebiotic envir onment . In fact, nonen -zymatic synthesis of both comp ound s has beenachieved (Or6 1965). Rather, we suggest that pre-biotic chemistry experimentation should focus onthe achievements of memb rane -bou nded systemscontaining catalyic and autocatalytic RNA or nu-cleic acid-like polymers (Schwartz and Orgel 1986)with similar properties, capable of self-maintenancein the presence of inorganic ions and those organiccompounds such as amino acids, ATP, and othersexpected to be available under putative prebioticconditions.

Accord ing to the concept developed here, the am-plification of ancestral replicase genes must h avepreceded the appearance of genes coding for proteinsinvolved in DNA synthesis and replication, e.g.,DN A primases and D NA polymerases (Lazcano etal. 1987, 1988). This genetic ampli ficat ion processcould have been enhanced by phage and plasmidtransfer or gene duplication in the absence of celldivision. Replicase activity found in DNA-depen-dent RNA polymerases supports the concept thatthey first evolved in polymeri zation o f RN A in theabsence of DNA . An early and ubiquitous role forthis class of enzy mes is suggested, mak ing t hem idealfor reconst ructi on of universal (e.g., bacterial, viral,and eukaryotic) phylogenies (Llaca et al. 1987).

Acknowledgments. It is a pleasure to acknowledge many con-versations with Drs. Harmke Kamminga, Roscoe Stribling, andGail Fleischaker. For related articles on the origin and early evo-

lution of life see Origin of Life and the Evolution of Cells (L.Margulis, R. Guerrero, and A. Lazcano, eds., Trebails de la So-cietat Catalana de Biologia, Volume 39). The research reportedhere has been supported in part by NASA grant NGR 44-005-002 to J.O., and NASA grant NGR 004-025, the Richard A.Lounsbery Foundation, and the Boston University GraduateSchool to L.M.

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Crick FHC (1968) The origin of the genetic code. J Mol Biol38:367-379DarnellJE, DoolittleWF (1986) Speculationson the early courseof evolution. Proc Natl Acad Sci USA 83:1271-1275Diener TO (1982) Viroids and their interaction with host cells.Annu Rev Microbiol 36:239-258Eichhorn GL, Tarien E, Butzow JJ (1971) Interaction of metalions with nucleic acids and related compounds. XVI. Specificcleavage effects in the depolymerization of ribonucleic acidsby zinc (II) ions. Biochemistry 10:2014--2019Eigen M, Schuster P (1977) The hypercycle--a principle ofnatural self-organization. Part A: emergenceofthe hypercycle.Naturwissenschaften 64:541-565Ferris JP, Usher DA (1983) Origins of life. In: Zubay G ted)Biochemistry. Addison Wesley, Reading MA, pp 1191-1241Fersht AR (1979) Fidelity of replication of phage CX 174 DNAby DNA polymerase III holoenzyme: spontaneous mutationsby misincorporation. Proc Natl Acad Sci USA 76:4946-4950

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2 8 9F e r s h t A R ( 1 98 3 ) E n z y m i c e d it i n g m e c h a n i s m s i n p r o t e in s y n -t h e s is a n d D N A r e p l i c a t i o n . I n : H u n t T , P r e n t i s S , T o o z e J

( ed s) D N A m a k e s R N A m a k e s p r o t e i ns . E l s e v i e r M e d i c a lP r e s s , C a m b r i d g e , p p 2 2 6 - 2 3 2F r e i db e r g E C ( 1 98 5 ) D N A r e pa i r. W H F r e e m a n , S a n F r a n c is c oG a u s t a d J E , V o g e l S N ( 1 9 8 2 ) H i g h e n e r g y s o l a r r a d i a t i o n a n dt h e o r i g i n o f l if e . O r i g i n s o f L i f e 1 2 : 3 - 8G r o s s m a n L ( 1 9 6 3 ) T h e e f f e c t s o f u l t r a v i o l e t - i r r a d i a t e d p o l y u r i -d y l i e a c i d i n c e l l -f r e e p r o t e i n s y n t h e s i s i n Esche r ichia col i I I .T h e i n f l u e n c e o f s p ec i f ic p h o t o p r o d u c t s . P r o c N a t l A c a d S c iU S A 5 0 : 6 5 7 - 6 6 4G u e r r i e r - T a k a d a C , G a r d i n e r K , M a r s h T , P a c e N , A l t m a n S( 1 9 8 3 ) T h e R N A m o i e t y o f r i b o n u c l e a s e P is t h e c a t a l y t ics u b u n i t o f t h e e n z y m e . C e l l 3 5 : 8 4 9 - 8 5 7H a l d a n e J B S ( 1 9 6 5 ) D a t a n e e d e d f o r a b l u e p r i n t o f t h e fi r sto r g a n i s m . I n : F o x S W ( e d ) T h e o r i g i n o f p r e b i o l o g i c a l s y s t e m sa n d t h e i r m o l e c u l a r m a t r i c e s . A c a d e m i c P re s s , N e w Y o r k , p p1 1 - 1 5H a l m a n n M , S a n c he z R A ; O rg e l L E ( 1 96 9 ) P h o s p h o r y l a t i o no f D - r ib o s e i n a q u e o u s s o l u t i o n. J O r g C h e m 3 4 : 3 7 0 2 - 3 7 0 3H a r t m a n H , L a w le s s J G , M o r r i s o n P ( e d s) ( 1 9 8 5 ) T h e s e a r c hf o r t h e u n i v e r s al a n c e st o rs . N A S A S P - 4 7 7 , W a s h i n g t o n D CH o l l a n d J , S p i n d l e r I G H o r o d y s k i F , G r a b a n E , N i c h o l S , V a n d e P o lS ( 1 98 2 ) R a p i d e v o l u t i o n o f R N A g e n o m e s . S c ie n c e 2 1 5:1 5 7 7 - 1 5 8 5J o y c e G F , S c h w a r t z A W , M i l l e r S L , O r g e l L E ( 1 9 8 7 ) T h e c a s ef o r a n a n c e s t ra l g e n e t i c s y s t e m i n v o l v i n g s i m p l e a n a l o g u e s o ft h e n u c l e o t i d e s . P r o c N a t l A c a d S c i U S A 8 4 : 4 3 9 8 - 4 4 0 2

K a m e r G , A r g o s P ( 1 9 8 4) P r i m a r y s t r u c t u ra l c o m p a r i s o n o fR N A - d e p e n d e n t p o l y m e r a s e s f r o m p l a n t , a n i m a l a n d b a c -t e r ia l v i r u s es . N u c l e i c A c i d s R e s 1 2 ( 1 8 ) : 7 2 6 9 - 7 2 8 2K n o l l A H , B a r g h o o r n E S ( 19 7 7) A r c h e a n m i c r o f o s s il s s h o w i n g

c e l l d i v i s i o n f r o m t h e S w a z i l a n d s y s t e m o f S o u t h A f r i c a. S c i -e n c e 1 9 8 : 3 9 6 - 3 9 8

K o r n b e r g A ( 1 98 0 ) D N A r e p li c a ti o n . W H F r e e m a n , S a n F r a n -c i sco

K r u g e r K , G r a b o w s k i P J , Z a u g A J , S a n d s J , G o t t s e h l i n D E , C e c hT R ( 1 9 8 2 ) S e l f - s p li c i n g R N A a u t o e x e i s i o n a n d a u t o c y c l i -z a t i o n o f t h e r i b o s o m a l R N A i n t e rv e n i n g s e q u e n ce o f Tetra-h y m e n a . C e l l 3 1 : 1 4 7 - 1 5 7

L a m m e r s M , F o l l m a n n H ( 1 9 83 ) T h e r i b o n u c l eo t i d e r e d u c ta s -e s - - a u n i q u e g r o u p o f m e t a l l o e n z y m e s e s s e n ti a l f o r c e l l p r o -l i f e ra t i o n . S t r u c t B o n d i n g 5 4 : 2 7 - 9 1

L a z c a n o , A ( 1 9 8 6 ) P r e b i o t i c e v o l u t i o n a n d t h e o r i g i n o f c e ll s .T r e b a l l s S o c C a t B i o l 3 9 : 7 3 - 1 0 3L a z c a n o A , O r 6 J , M i l l e r S L ( 1 9 8 3 ) P r i m i t i v e E a r t h e n v i r o n -m e n t s : o r g a n i c s y n t h e s e s a n d t h e o r i g i n a n d e a r l y e v o l u t i o no f l i fe . P r e c a m b r i a n R e s 2 0 : 2 5 9 - 2 8 2

L a z c a n o A , V a l v e r d e V , F a s t a g J , G a r i g l i o P , R a m i r e z C , O r 6 J( 1 9 8 7 ) M o l e c u l a r e v o l u t i o n o f n u c l e i c a c i d p o l y m e r a s e s . I n :E i r i c h F , P o n n a m p e r u m a C ( ed s) P r e b i o l o g i c a l o r g a n i z a t i o n .P r o c ee d i n g s o f t h e V I I I C o l l e ge P a r k C o l l o q u i u m o n C h e m i c a lE v o l u t i o n ( i n p r e ss )

L a z c a n o A , F a s t a g J , G a r i g l i o P , R a m i r e z C , O r 6 J ( 1 9 8 8 ) O nt h e e a r ly e v o l u t i o n o f R N A p o l y m e r a s e . J M o l E v o l ( in p re s s )

L i n d a h l T ( 1 98 2 ) D N A r e p ai r e n z y m e s . A n n u R e v B i o c h e m5 1 : 6 1 - 8 7

L l a c a V , S i l v a E , L a z c a n o A , R a n g e l L M , G a r i g l i o P , O r 6 J( 1 9 8 7) I n s e ar c h o f t h e a n c e st r a l R N A p o l y m e r a s e : a n e x -p e r i m e n t a l a p p r o a c h . I n : E i r i c h F , P o n n a m p e r u m a C ( e d s )P r e b i o l o g i c a l o r g a n i z a t i o n . P r o c e e d i n g s o f t h e V I I I C o l l e g eP a r k C o l l o q u i u m o n C h e m i c a l E v o l u t i o n ( i n p r e s s )

L o e b L A , K u n k e l T A ( 1 98 2 ) F i d e l it y o f D N A s y n t he s is . A n n uR e v B i o c h e m 5 1 : 4 2 9 - 4 5 7M a r A , D w o r k i n J , O r 6 J ( 1 9 8 7) N o n - e n z y m a t i c s y n t h e s is o ft h e c o e n z y m e s u r i d i n e d i p h o s p h a t e g l u c o s e a n d c y t i d i n e d i -p h o s p h a t e c h o l i n e a n d o t h e r p h o s p h o r y l a t e d m e t a b o l i c i n -t e r m e d i a t e s . O r i g i n s o f L if e a n d E v o l u t i o n o f t h e B i o s p h e r e(in press)

M a r g u l is L ( 1 98 1 ) S y m b i o s i s i n c e ll e v o l u t i o n . W H F r e e m a n ,S a n F r a n c i s c oM a r g u l i s L , G u e r r e r o R ( 1 98 8 ) F r o m o r ig i n s o f l i f e t o e v o l u t i o no f m i c r o b i a l c o m m u n i t i e s : a m i n i m a l i s t a p p r o a c h . I n : E i r i c hF , P o n n a m p e r u m a C (e d s ) P r e b i o l o g i c a l o r g a n i z a t i o n . P r o -c e e di n g s o f t h e V I I I C o l l e g e P a r k C o l l o q u i u m o n C h e m i c a lE v o l u t i o n ( i n p r e s s )M a r g u l i s L , S a g a n D ( 1 9 8 6 ) T h e o r i g i n s o f s e x . Y a l e U n i v e r s i t yP r es s, N e w H a v e n

M a r g u l i s L , W a l k e r J C G , R a m b l e r M ( 1 9 7 6 ) A r e a s s e s s m e n to f t h e r o l e s o f o x y g e n a n d u l t r a v i o l e t l i g h t in P r e c a m b r i a ne v o l u t io n . N a t u r e 2 8 4 : 6 2 0 - 6 2 4M c L a r e n A D , S h ug a r D ( 1 96 4 ) P h o t o c h e m i s t r y o f p r o t e in s a n dn u c l e i c a c i ds . P e r g a m o n , O x f o r dM i l d v a n A , L o e b L ( 1 97 9 ) T h e r o l e o f m e t a l i o n s i n th e m e c h -a n is m s o f D N A a n d R N A p o ly m e r as e s. C R C C r i t R e v B i o -c h e m 6 : 2 1 9 - 2 4 4M i l l e r S L , O r g e l L E ( 1 9 7 4 ) T h e o r i g i n s o f l i f e o n E a r t h . P r e n t i c e -H a l l , E n g l e w o o d C l i f fs N JO l i v e r a B M ( 1 97 8 ) D N A i n te r m e d i a t e s a t t h e Escher ichia col ir e p l ic a t i o n f or k : ef fe c t o f d U T P . P r o c N a i l A c a d S c i U S A 7 5 :2 3 8 - 2 4 3O n o J , W i l s o n R G , G r o s s m a n L ( 1 9 6 5 ) E f f ec t s o f u l t r a v i o l e tl i g h t o n t h e t e m p l a t e p r o p e r t i e s o f p o l y c y t i d y l i c a c i d . J M o lB i o l 1 1 : 6 0 0 - 6 1 2O p a r i n A I ( 1 9 6 1) L i f e : i t s n a t u r e , o r ig i n a n d d e v e l o p m e n t .O l i v e r a n d B o y d , E d i n b u r g hO r ge ] L E ( 1 9 6 8 ) E v o l u t i o n o f t h e g e n e t i c a p p a r a t u s . J M o l B i o l3 8 : 3 8 0 - 3 9 3O r g e l L E , L o h r m a n n R ( 1 9 7 4 ) P r e b i o t i c c h e m i s t r y a n d n u c l e i ca c i d r e p li c a t i o n . A c e C h e m R e s 1 : 3 6 8 - 3 7 7O r 6 J ( 1 9 6 5 ) S t a g es a n d m e c h a n i s m s o f p r e b i o l o g i c a l o r g a n i cs y n t h e si s . I n : F o x S W ( e d ) T h e o r i g i n o f p r e b i o l o g i c a l s y s t e m sa n d t h e i r m o l e c u l a r m a t r i c e s . A c a d e m i c P r e s s , N e w Y o r k , p p137-161O r 6 J , L a z c a n o A ( 1 9 8 4 ) A m i n i m a l l i v i n g s y s t e m a n d t h eo r i g i n o f a p r o t o c e l l. A d v S p a c e R e s 4 : 1 6 7 - 1 7 6O r 6 J , L a z c a n o A ( 1 9 8 8 ) A h o l i st i c p r e c e l l u l a r o r g a n i z a t i o nm o d e l . I n : E i r i c h F , P o n n a m p e r u m a C ( e d s ) P r e b i o l o g i c a lo r g a n i z a t i o n . P r o c e e d i n g s o f t h e V I I I C o l l e g e P a r k C o l l o -q u i u m o n C h e m i c a l E v o l u t i o n ( i n p r e s s )

P a c e N , M a r s h T ( 1 9 8 5 ) R N A c a t a l y s is a n d t h e o ri g i n o f l i fe .O r i g i n s L i f e 1 6 : 9 7 - 1 1 6P e a r s o n M , J o h n s H E ( 19 66 ) S u p p r e s s i o n o f h y d r a t e a n d d i m e rf o r m a t i o n i n u l t r av i o l e t -i r r a d ia t e d p o l y ( A + U ) r e l a t iv e t op o l y ( U ). J M o l B i o l 2 0 : 2 1 5 - 2 2 9R a m b l e r M , M a r g u l i s L ( 1 9 8 0 ) B a c t e r i a l r e s i s ta n c e to U V r a -d i a t i o n u n d e r a n a e r o b i o s i s : i m p l i c a t i o n s f o r p r e - P h a n e r o z o i ce v o l u t i o n . S c i e n c e 2 1 0 : 6 3 8 - 6 4 0R e a n n e y D C ( 1 97 9 ) R N A s p l ic i n g a n d p o l y n u c l e o ti d e e v o l u -t i on . N a t u r e 2 2 7 : 5 9 7 - 6 0 0R e a n n e y D C ( 1 98 2 ) T h e e v o l u t i o n o f R N A v i ru s e s. A n n u R e vM i c r o b i o l 3 6 : 4 7 - 7 3R e m s e n J F , C e r u t ti P A ( 1 97 2 ) U l t r a v i o l e t i n a c t i v a t io n a n dm i s c o d i n g o f ir r a d ia t e d R 1 7 - R N A i n v i t r o . B i o c h e m B i o p h y sR e s C o m m u n 4 8 :4 3 0 -- 4 36R i c h A ( 1 96 2 ) O n t h e p r o b l em s o f e v o l u t i o n a n d b i o c h e m i c a li n f o r m a t i o n t r a n sf e r . I n : K a s h a M , P u l l m a n B ( e ds ) H o r i z o n si n b i o c h e m i s t r y . A c a d e m i c P r e s s, N e w Y o r k , p p 1 0 3 - 1 2 6

S a e n g e r W ( 1 9 8 4) P r i n c i p l e s o f n u c l e i c a c i d s t r u c t u re . S p r in g e r -V e r la g , N e w Y o r kS c h o p f J W ( e d ) ( 1 9 8 3 ) T h e E a r t h s e a r l i e s t b i o s p h e r e : it s o r i g i na n d e v o l u t i o n . P r i n c e to n A c a d e m i c P r e s s, P r i n c e t o n N JS c h o p f J W , P a c k e r B M ( 1 9 8 7) E a r l y A r c h e a n (3 .3 b i l l i o n t o3 .5 b i ll ion-year -o ld ) mic ro foss i l s f rom the Wa rraw oona g roup ,A u s t r a l i a . S c i e n c e 2 3 7 : 7 0 - 7 3

S c h w a r tz A W ( 1 98 6 ) S p o n t a n e o u s o l i g o m e r i z a ti o n o f p u r i n ed e r i v a t i v e s . A b s t r a c t s o f t h e F i f t h I S S O L ( I n t e r n a t i o n a l S o .c i e t y f o r t h e S t u d y o f t h e O r i g i n o f L i fe ) M e e t i n g , B e r k e l e yCA , Ju ly 21-25 , 1986 , p 155

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2 9 0S c h w a r tz A W 1 9 87 ) M i n i m a l r e q u i r e m e n t s f o r m o l e c u l a r i n -

f o r m a t i o n t r a n s f e r. A d v S p a c e R e s 6 i n p r e s s)S c h w a r t z A W , O r g e l L E 1 9 8 6 ) T e m p l a t e - d i r e c t e d s y n t h e s i s o fn o v e l , n u c l e i c a c i d - l i k e s tr u c t u re s . S c i e n c e 2 2 8 : 5 8 5 - 5 8 7

S e t l o w R B 1 9 6 8) T h e p h o t o c h e m i s t r y , p h o t o b i o l o g y a n d r e p a iro f p o ly n u c l e o t i d e s . P r o g N u c l e i c A c i d R e s M o l B i o l 8 : 2 5 7 -295S h l o m a i J , K o r n b e r g A 1 9 7 8) D e o x y u r i d i n e t r ip h o s p h a t a se o fE s c h e r i c h i a c o l i: p u r i f i c a ti o n , p r o p e r t i e s a n d u s e a s a r e a g e n tt o r e d u c e u r a c i l i n c o r p o r a t i o n i n t o D N A . J B i o l C h e m 2 5 3 :3 3 0 5 - 3 3 1 2S h u g a r D 1 9 6 0 ) P h o t o c h e m i s t r y o f n u c l e i c a c i d s a n d t h e i rc o n s t i t u e n ts . I n : C h a r g a f f E , D a v i d s o n J N e ds ) T h e n u c l e i ca c i d s , v o l I I I . A c a d e m i c P r e s s , N e w Y o r k , p p 3 9 - 1 0 4S i n g e r B , K u s m i e r e k J T 1 9 8 2 ) C h e m i c a l m u t a g e n e s i s . A n n uR e v B i o c h e m 5 2 : 6 5 5 - 6 9 3S p i r i n A S 1 9 8 6 ) R i b o s o m e s tr u c t u r e a n d p r o te i n b i o y n t h e s i s .B e n j a m i n C u m m i n g s, M e n l o P a rk C AS p r e n g e l G , F o l l m a n n H 1 9 8 1 ) E v i d e n c e f o r t h e r e d u c t i v ep a t h w a y o f d e o x y r i b o n u c l e o t i d e s y n t h e s i s in a n a r c h a e b a c -t e r i u m . F E B S L e t t 1 3 2 : 2 0 7 - 2 0 9

S p r i n g g at e C F , L o e b L A 1 9 7 5 ) O n t h e f i d e li t y o f t r a n s c r ip t i o nb y t h e E s c h e r i c h i a c o l i r i b o n u c l e i c a c i d p o l y m e r a s e . J M o lB i o l 9 7 : 5 7 7 - 5 9 1S t e i n h au e r D A , H o l l a n d J J 1 9 8 7) R a p i d e v o l u t i o n o f R N A

v i r u s e s . A n n u R e v M i c r o b i o l 4 1 : 4 0 9 - - 4 3 3T y e B K , C h ie n J , L e h m a n I R , D u n c a n B K , W a r n e r H R 1 9 7 8a )U r a c i l i n c o r p o r a t i o n : a s o u r c e o f p u l s e -l a b e l e d D N A f r ag -m e n t s i n t h e r e p l i c a t i o n o f t h e E s c h e r i c h i a c o l i c h r o m o s o m e .P r o c N a t l A c a d S c i U S A 7 5 : 2 3 3 - 2 3 9T y e B K , N y m a n P O , L e h m a n I R 1 9 7 8 b) E x c i s io n r e p a ir o fu r a c i l d u r i n g r e p l i c a t i o n o f C X 1 7 4 D N A i n v i t r o . B i o c h e mB i o p h y s R e s C o m m u n 8 2 : 4 3 4 - - 4 3 7

U s h e r D A 1 9 7 7 ) E a r l y c h e m i c a l e v o l u t i o n o f n u c l e i c a c i d s.S c i e n c e 1 9 6 : 3 1 1 - 3 1 3

V a r e l a F , M a t u r a n a H R 1 9 7 4 ) A u t o p o i e s i s : t h e o r g a n i z a t i o no f li v i n g s y st e m s , i t s c h a r a c t e r i z a t i o n a n d a m o d e l . B i o -S y s t e m s 5 : 1 8 7 - 1 9 6V o e t D , G r a t z a r W B , C o x R A , D o t y P 1 9 6 3) A b s o r p t i o n s pe c -t r a o f n u c l e o t id e s , p o l y n u c l e o t i d e s a n d n u c l e i c a c id s i n t h ef a r u l t r a v i o l e t . B i o p o l y m e r s 1 1 9 3 - 2 0 8

W a c k e r A , D e ll w e g D , T r a g e r L , K o m h a u s e r A , L o d e m a n n E ,T u r c k G , S e i z e r R , C h a n d r a P , I s h i m o t o M 1 9 6 4 ) O r g a n i cp h o t o c h e m i s t r y o f n u c le i c a c id s . P h o t o c h e m P h o t o b i o l 3 : 3 6 9 -3 8 2

W h i t e D H , E r ic k s o n J C 1 9 8 1) E n h a n c e m e n t o f p e p t i d e b o n df o r m a t i o n b y p o l y r i b o n u c l e o t i d e s o n c l a y s u r f a c e s i n f l u c -t u a t i n g e n v i r o n m e n t s . J M o l E v o l 1 7 : 1 9 - 2 6W h i t e H B 1 9 7 6 ) C o e n z y m e s a s f o s s il s o f a n e a r l ie r m e t a b o l i cs t a te . J M o l E v o l 7 : 1 0 1 - 1 0 4W h i t e H B 1 9 82 ) E v o l u t i o n o f c o e n z y m e s a n d t h e o r i g in o fp y r i d i n e n u c l e o t i d e s. I n : E v e r s e J, A n d e r s o n B , Y o u K S e ds )

T h e p y r i d i n e n u c l e o t i d e c o e n z y m e s . A c a d e m i c P r e s s , N e wY o r k , p p 2 - 1 7W o e s e C R 1 9 6 7 ) T h e o r i g i n s o f t h e g e n e t i c c o d e . H a r p e r a n dR o w , N e w Y o r kZ a u g , A J , C e c h T R 1 9 8 5 ) O l i g o m e r i z a t i o n o f i n t e r v e n i n g s e -

q u e n c e R N A m o l e c u l e s in t h e a b s e n c e o f p r o t e i n s . S c i e n c e2 2 9 : 1 0 6 0 - 1 0 6 4 .Z a u g, A J , C e c h T R 1 9 8 6) T h e i n te r v e n i n g s e q u e n c e o f t e t r ah y r n e n a i s a n e n z y m e . S c i e n c e 2 3 1 : 4 7 0 - 4 7 5 .

R e c e i v e d O c t o b e r 2 3, 1 9 8 7 / R e v i s e d a n d a c c e p t e d F e b r u a r y 2 6 ,1988