Theory Teaching Session 1

8/10/2019 Theory Teaching Session 1

http://slidepdf.com/reader/full/theory-teaching-session-1 1/99

Genetic Predisposition to Cancer

Dr. Jordi Surrallés, Jan 2015

Topics:

1. Familiar cancer ersus cancer predisposition s!ndromes

2. D"# repair pat$%a!s and $uman disease&. Tar'etin' D"# repair in cancer t$erapeutics. S!nt$etic let$alit!

(. Genetic strate'ies to identi)! cancer suscepti*ilit! 'enes

5. +enc$ to *eadside researc$ in Fanconi anemia







16 FEBRUARY 2001 VOL 291 SCIENCE





D"# dama'e response



D"# dama'e response

From: $ttp:%%%.si'maaldric$.comtec$nical-documentsarticles*io)ilesdna-dama'e-and-repair.$tml



Cell c!cle durin' D"# dama'e response

From the followin !rti"le#

T$e impact o) a ne'li'ent G2 c$ec/point on 'enomic insta*ilit! and cancer

induction

ar/us *ric$ Penn! #. Je''o

"ature 3eie%s Cancer 4, 61-67 8"oem*er 20049




D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et"icola J. Curtin

"ature 3eie%s Cancer 12, 01-14 8Decem*er 20129




o% nucleotide e;cision repair protects a'ainst cancer

<rrol C. Fried*er'"ature 3eie%s Cancer 1, 22-&&



Sources o) D"# dama'e and t$eir repair


D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et"icola J. Curtin




ain D"# lesions and correspondin' D"#-

dama'e-repair pat$%a!s

Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatment

Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&



Mutations in DNA repair genes

Defective DNA repairGenomic instability

Cell death or Cancer

Somatic level:

sporadic cancer in

the general

population

Germinal level: cancer

predisposition DNA

repair syndromes





Disease evolution in Fanconi Anemia

Kutler et al., Blood, 2003



Mutations in DNA repair genes

Defective DNA repairGenomic instability

Cell death or Cancer

Somatic level:

1 mutation

Germinal level:

1 mutation





+reast cancer ris/ in +3C#2 mutation carriers



#n'elina Jolie is a +3C# mutation carrier



Familiar cancer





D"# repair pat$%a!s

• $ire"t re%!ir-Trans)erases

-P$otol!ases

• $o&'le Str!n( Bre!) *$SB+ re%!ir

-"on-$omolo'ous end ?oinin' 8"<J9

-omolo'ous recom*ination 839

•

-s$ort patc$ +<3

-lon' patc$ +<3

• N&"leoti(e e-"i,ion re%!ir *NER+

-Glo*al 'enome "<3 8GG-"<39-Transcription coupled "<3 8TC-"<39

• .i,m!t"h re%!ir *..R+

•ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+



D"# repair pat$%a!s


-P$otol!ases




•

-s$ort patc$ +<3

-lon' patc$ +<3



• .i,m!t"h re%!ir *..R+

•ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+



@6-alAuil G 8#:T9

@(-alAuil T 8C:G9

-me 'uan na me rans erasa -





D"# repair pat$%a!s


-P$otol!ases


-"<J

-3

•

-s$ort patc$ +<3

-lon' patc$ +<3



• .i,m!t"h re%!ir *..R+

• ICL re%!ir *F!n"oni !nemi!/BRCA %!thw!+



DS+ repair *! "<J and $omolo'ous recom*ination


C$romatin d!namics and t$e preseration o) 'enetic in)ormationJessica #. Do%ns, ic$el C. "ussen>%ei' #ndré "ussen>%ei'

"ature ((4, 751-75821 June 20049



DS+ repair *! "<J and $omolo'ous recom*ination


C$arit! *e'ins at $ome: non-codin' 3"# )unctions in D"# repair

Dipan?an C$o%d$ur!, Boun' <un C$oi arie <e +rault

"ature 3eie%s olecular Cell +iolo'! 1(, 11-17 8arc$ 201&9





33:

$ttp:%%%.!outu*e.com%atc$!E@C5%

"<J:

$ttp:%%%.!outu*e.com%atc$?@rm-sH-B?'



@ri'in o) D"# dou*le strand *rea/s 8DS+9



Ataxia telangiectasia (ATM)



Nijmegen breakage syndrome (NBS1)



+loom s!ndrome 8+9



Seckle syndrome (ATR)





"<J can *e error prone

From: $ttp:%%%.si'maaldric$.comtec$nical-documentsarticles*io)ilesdna-dama'e-and-repair.$tml



Gene editin' %it$ en'ineered nucleases is

*ased on DS+ repair 8T#<", C3ISP39

From: $ttp:%%%.tool'en.com$tml/ortec$nolo'!'enEen'Enuc.p$p



D"# repair pat$%a!s



D"# repair pat$%a!s


-P$otol!ases




•

-s$ort patc$ +<3

-lon' patc$ +<3



• .i,m!t"h re%!ir *..R+




+ase e;cision repair 8+<39

Glicosilasa:

corte enlace 'licoslico

entre la *ase ! la ri*osa

de?a un sitio #P

#P endonucleasa:

e;tremo 5K del sitio #P

D"# polL:

rellena el $ueco

elimina el 'rupo ri*osa-)os)ato8actiidad liasa9

Comple?o M3CC1-li'asaIII:

sellado de la mella



+<3: t%o pat$%a!s



+<3: t%o pat$%a!s





+<3 8SP9

$ttp:%%%.!outu*e.com%atc$42oT6"70ic

+<3 8P9

$ttp:%%%.!outu*e.com%atc$'(/$3@a@@6clist

PF&FF#<#+D7C1(0

D"# repair pat$%a!s



D"# repair pat$%a!s

•$ire"t re%!ir

-Trans)erases

-P$otol!ases




•

-s$ort patc$ +<3-lon' patc$ +<3



• .i,m!t"h re%!ir *..R+


Nucleotide excision repair (NER)



Nucleotide excision repair (NER)

recognition

dual incision

UV

excision

DNA synthesis

ligation







Initial Steps of Transcription-Coupled NEREarly Stages of Global GenomeRepair

Fi l St f E k ti NER



Final Steps of Eukaryotic NER



"<3 8GG9

$ttp:%%%.!outu*e.com%atc$*'7")@2N

"<3 and $uman disease




D"# repair de)icienc! and neurolo'ical diseasePeter J. cHinnon

"ature 3eie%s "euroscience 10, 100-112 8Fe*ruar! 20079



Xeroderma pigmentosum



Cockayne syndrome



"<3

GG3 TC3

Cockayne syndromeXeroderma pigmentosum

Skin cancer No cancer!

D"# repair pat$%a!s



• $ire"t re%!ir

-Trans)erases

-P$otol!ases




•




• .i,m!t"h re%!ir *..R+




D"# pol $ae proo)-readin' actiit!



D"# pol $ae proo) readin' actiit!



he E,"heri"hi! "oli .ethl$ire"te(



.i,m!t"h Re%!ir Re!"tion

T$e oerall repair reaction can *e diided into seeral

steps:

• mismatc$-de endent incision o) t$e unmet$ lated

strand at a $emi-met$!lated G#TC site.

• <;cision o) t$at portion o) t$e incised strand spannin't$e sin'le-strand *rea/ and t$e mispair.

• 3epair o) t$e ensuin' 'ap *! D"# s!nt$esis and

li'ation.

uman mismatc$ repair 839 pat$%a!




#ID and mismatc$ repair in anti*od! diersi)ication

#l*erto artin att$e% D. Sc$ar)) "ature 3eie%s Immunolo'! 2, 605-61( 8#u'ust 20029



3

$ttp:%%%.!outu*e.com%atc$BS6<HnNc0

$ttp:%%%.!outu*e.com%atc$d'P$1Ai'4s

icrosatellite insta*ilit!



!

Distinct molecular pat$%a!s )or t$e deelopment o)



de)ectie D"# 3 and SI- in colon cancer

Sinicrope, F. #. 820109 D"# mismatc$ repair and ad?uant c$emot$erap! in sporadic colon cancer

Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2007.2&5

D"# repair pat$%a!s



• $ire"t re%!ir

-Trans)erases

-P$otol!ases




•



-Glo*al 'enome "<3 8GG-"<39

-Transcription coupled "<3 8TC-"<39

• .i,m!t"h re%!ir *..R+


Interstrand crosslink repair (ICLR)



Fork stalling

Unhooking

Translesion sythesis

Recombination

Fanconi anemia



FA-A FA-C

D"# repair as a t$erapeutic tar'et



Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatment

Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&

D"# repair pat$%a!s inoled in repairin' to;ic D"#

lesions )ormed *! cancer treatments



elleda! et al. "ature 3eie%s Cancer , 17&-20( 8arc$ 2009

S!nt$etic let$alit! in cancer treatment




D"# repair d!sre'ulation )rom cancer drier to t$erapeutic tar'et

"icola J. Curtin






D"#-repair *iomar/ers and t$erapeutic implication



Postel-=ina!, S. et al. 820129 T$e potential o) e;ploitin' D"#-repair de)ects )or optimi>in' lun' cancer treatmentNat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2012.&

"<3 in cancer and as tar'et in cancer treatment





"icola J. Curtin


+<3 in cancer and as tar'et in cancer treatment




"icola J. Curtin


3 in cancer and as tar'et in cancer treatment





"icola J. Curtin


3 in cancer and as tar'et in cancer treatment





"icola J. Curtin


DS+ repair in cancer and as tar'et in cancer treatment





"icola J. Curtin


S!nt$etic let$alit! in tumors )rom BRCA1 and BRCA2

mutation carriers treated %it$ P#3P in$i*itors



Nature Medicine 17, 283–284 (2011)



Nature Biotechnology 29,373–374(2011)

ec$anism o) s!nt$etic let$alit! *et%een BRCA



de)icienc! and P#3P in$i*ition

+aner?ee, S.et al.

820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancerNat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116







<))ects o) P#3P in$i*ition on BRCA2-mutant cells



+aner?ee, S. et al. 820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancer

Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116

3AR3 inhi'itor 4 3AR3 inhi'itor

CT scans o) t%o patients %it$ adanced oarian



cancer a)ter P#3Pi t$erap!

+aner?ee, S. et al. 820109 a/in' t$e *est o) P#3P in$i*itors in oarian cancer

Nat. Rev. Clin. Oncol. doi:10.10&nrclinonc.2010.116

<;amples o) DD3 in$i*itors in clinical use or in deelopment



Nature 481, 287–294 (19 January 2012)



<;periments to *e done:



• = sensitiit! o) MP de)icient s/in cells

•#*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells

•

tumor cells de)icient in t$e F# pat$%a! on ICrepair

• P#3P in$i*ition )or selectie /illin' o) +3C#1

de)icient tumor cells• omolo'ous recom*ination repair o) DS+







60%

90%

i n i n g 6 - 4 P P

f o c i

60%

90%

i n i n g 6 - 4 P P

f o c i

4 8 12 16 20 2400

30%

% o

f c e l l s c

o n t a

Time (h) after UV irradiation

4 8 12 16 20 2400

30%

% o

f c e l l s c

o n t a

Time (h) after UV irradiation





• #*normal repair /inetics o) =-li'$t inducedD"# dama'e in MP de)icient s/in cells

•






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..C 4 ..C

51# =682:

524.# ;687:

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524.# 1087:

51# 668:

524.# 298;:

F A 2 A 3

! t i e n t

4 FANCA 4 FANCA






•











•




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Theory Teaching Session 1