Structural and Functional Insight into Proliferating Cell Nuclear Antigen

A 2016⎪Vol. 26⎪No. 0

J. Microbiol. Biotechnol. (2016), 26(4), 637–647http://dx.doi.org/10.4014/jmb.1509.09051 Research Article jmbReview

Structural and Functional Insight into Proliferating Cell Nuclear AntigenSo Young Park1,2†, Mi Suk Jeong1†, Chang Woo Han1, Hak Sun Yu2, and Se Bok Jang1*

1Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea2Department of Parasitology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea

Introduction

Proliferating cell nuclear antigen (PCNA) is a highly

conserved protein in archaebacteria and several eukaryotic

species [67]. Studies of all known PCNAs show that they

are conserved in amino acid sequences, functions, and

structures [5, 54, 68]. PCNA was initially reported as a

fundamental auxiliary protein for the processes of DNA

replication and repair, and it works as a DNA sliding

clamp; that is, it stabilizes the interaction with other

proteins through a sliding platform [14, 30]. The DNA

sliding clamps perform an essential function in DNA

metabolic processes, and are found in eukaryotes,

prokaryotes, and archaea [24, 31, 37, 71, 74, 83]. They are

ring-shaped six-domain proteins that encircle duplex DNA

and enable highly processive DNA replication by serving

as binding sites for DNA polymerases. As a DNA clamp,

PCNA acts as a scaffold protein that organizes various

components for DNA replication, chromatin remodeling,

DNA damage repair, and cell cycle progression [47, 55].

PCNA is a homotrimer ring and it forms in a head-to-tail

arrangement of three monomers [36, 47]. This ring-shaped

trimeric PCNA is loaded onto DNA. The inner surface of

the PCNA is formed by 12 positively charged α-helices that

interact with DNA, and the outer layer contains 54 β-sheets

and interdomain-connecting loops (IDCLs) for protein-

protein interactions [47, 82]. In addition, PCNA interacts

with several translesion synthesis (TLS) DNA polymerases

[55, 84] and participates in repair of DNA that has been

damaged by chemotherapy agents [78], thereby conferring

chemotherapy resistance. PCNA was initially discovered to

be an antigen to the autoimmune disease systemic lupus

erythematosus [46, 71]. The level of expression of PCNA

changes during cell cycles and is associated with cell

proliferation or transformation [4]. A great deal of work

was conducted to determine the roles of PCNA in DNA

replication and one of the functions identified was a sliding

clamp for DNA polymerase δ [54, 68]. Deregulation of

PCNA expression is a hallmark of many proliferative

diseases and PCNA acts as a general proliferative marker,

particularly in determining cancer prognosis [34, 65].

The homotrimeric complex of PCNA consists of three

Received: September 17, 2015

Revised: December 18, 2015

Accepted: December 23, 2015

First published online

December 23, 2015

*Corresponding author

Phone: +82-51-510-2523;

Fax: +82-51-581-2544;

E-mail: [email protected]

†These authors contributed

equally to this work.

pISSN 1017-7825, eISSN 1738-8872

Copyright© 2016 by

The Korean Society for Microbiology

and Biotechnology

Proliferating cell nuclear antigen (PCNA) is a critical eukaryotic replication accessory factor

that supports DNA binding in DNA processing, such as DNA replication, repair, and

recombination. PCNA consists of three toroidal-shaped monomers that encircle double-

stranded DNA. The diverse functions of PCNA may be regulated by its interactions with

partner proteins. Many of the PCNA partner proteins generally have a conserved PCNA-

interacting peptide (PIP) motif, located at the N- or C- terminal region. The PIP motif forms a

310 helix that enters into the hydrophobic groove produced by an interdomain-connecting

loop, a central loop, and a C-terminal tail in the PCNA. Post-translational modification of

PCNA also plays a critical role in regulation of its function and binding partner proteins.

Structural and biochemical studies of PCNA-protein will be useful in designing therapeutic

agents, as well as estimating the outcome of anticancer drug development. This review

summarizes the characterization of eukaryotic PCNA in relation to the protein structures,

functions, and modifications, and interaction with proteins.

Keywords: PCNA, DNA, structure, function, interaction

638 Park et al.

J. Microbiol. Biotechnol.

domains; the amino-terminal domain, the IDCL, and the

carboxyl-terminal domain. The IDCL links the N- and C-

terminal domains and makes significant contributions to

the diverse cellular activity of PCNA [21]. Investigations of

PCNA have shown that the IDCL is a major interaction site

for various binding proteins [19], including polymerases

Polδ, p21, DNA-(cytosine-5) methyltransferase (MeCTr),

DNA ligase 1 (LIG1), flap endonuclease 1 (FEN1), cyclin-

dependent kinase 2 (CDK2), and cyclin D, etc. Whereas it is

known that many proteins and peptides bind to PCNA

through conserved motifs, the binding mechanisms

between PCNA and partner proteins are still unknown. A

large part of the PCNA-binding proteins comprises a

conserved motif referred to as the PCNA-interacting

peptide (PIP) box [24, 28, 49]. The IDCL of PCNA is the

binding site that contains the consensus PIP-box motif,

Q-X-X-(I/L/M)-X-X-(F/Y)-(F/Y) [32, 84]. The PIP-box has

I/L/M small hydrophobic residues, F/Y aromatic side

chains, and X residues. Recently, another PCNA-binding

motif termed the KA-box [39], K-A(A/L/I)-(A/L/Q)-x-x-

(L/V), has been identified. It is also introduced in many

PCNA-interacting proteins and is associated with the

canonical PIP-box [62, 87]. Polη, Polι, and Polκ have a

noncanonical PIP-box sequence [25]. Other binding regions

are placed in the N-terminal region, including the

interaction between α-helices of PCNA and cyclin D [52].

In addition, the region is in the C-terminal region, which is

important for the interaction with Polε, CDK2, replication

factor C (RFC), and growth-arrest and DNA-damage-

inducible protein 45 (Gadd45) [39, 52]. This review focuses

on the structural characterization and function of PCNA.

The information will be useful in designing therapeutic

agents, as well as estimating the outcome of anticancer

drug development.

Major Role of PCNA in the DNA Replication and

Repair System

PCNA is a crucial replication factor that binds with many

partner proteins included in DNA replication and damage

repair. In mammals, DNA replication is started by

phosphorylation of the origin recognition complex at the

site of origin [8, 67]. PCNA is a homolog of the β subunit of

the DNA polymerases in prokaryotes, known as the sliding

clamp for eukaryotic DNA polymerases δ/ε [54, 68]. It

interacts with the Polδ switch to facilitate extension of

Okazaki fragments [79]. PCNA functions as a clamp

platform for polymerases δ and ε as well as a variety of

proteins at the replication. It is loaded onto DNA junctions

by the action of a multiple clamp loader, RFC, which

couples with ATP hydrolysis to open and close the PCNA

ring during replication and repair [23, 41]. PCNA exists as

stable trimers that form a closed ring with a central hole,

which encircles the DNA (Fig. 1). It interacts with and

recruits FEN1 and LIG1, which are required for Okazaki

fragment processing (Fig. 2) [39]. The PCNA complex for

the Okazaki fragment maturation ensures the directivity of

replication, and PCNA is a crucial moderator of DNA

replication. During the DNA replication, synthesis over

damaged templates is accomplished by polymerases via

translesion synthesis (TLS) [56, 90]. Conserved TLS

polymerases identified in several species includes Y-family

polymerases η, ι, and κ, and Rev1 and Rev7 as well as B-

family polymerase ζ [7, 53]. Mono-ubiquitination of PCNA

Fig. 1. Structural features of PCNA.

(A) Front view of the three-dimensional structure of human PCNA in

complex with the p21 peptide (PDB ID, 1AXC). PCNA is a trimeric

molecule, with each monomer containing a PIP-box binding site

located between the C-terminus of the protein and the interdomain

connector loop (IDCL). The side view shows the location of the IDCL

on the front side of PCNA and the extended loops on the back side.

The N-terminal domain is colored in red, the C-terminal domain is

colored in blue, and the IDCL is colored in green. (B) The molecular

surface of PCNA showing its charge distribution. Negatively charged

residues are shown in red; positively charged residues are shown in

blue.

Structural and Functional Roles of PCNA 639

April 2016⎪Vol. 26⎪No. 4

stimulates the recruitment of TLS polymerase to the

replication fork [23, 63]. PCNA provides the central stool

on which TLS polymerase can interact to acquire access to

the replicative stalled at the lesion site and to perform their

roles in modulation of different lesion bypass processes.

TLS polymerase works individually or in pairs according

to the damage type. PCNA enhances polymerase activity,

resulting in up-regulated ability of nucleotide on the other

sites to the damaged template [53, 61].

PCNA plays an important role in the DNA damage

repair and DNA replication system [72]. The major

metabolic pathways for DNA repair systems implicate

nucleotide excision repair (NER), base excision repair

(BER), double-strand break repair, and mismatch repair

(MMR) [10, 39, 85]. DNA damage by certain chemicals and

UV-irradiation results in bulky lesions, which are then

repaired via the NER pathway. During this process, PCNA

binds to the endonuclease, XPG (xeroderma pigmentosum

complementation group G) and facilitates new DNA

fragment resynthesis, which occurs after reactions catalyzed

by XPG [20]. PCNA is specifically loaded at the major

cellular activity site of the XPG 3’-incision to the lesion for

repairing [39]. BER is responsible for replacing chemically

altered nucleotide bases in DNA and can operate in either

short- or long-patch modes. PCNA is associated with DNA

repair in long-patch mode, which involves a DNA

polymerase δ/ε-dependent mechanism. It has been observed

to bind with various BER proteins, such as AP-endonuclease

1 (APE1), AP-endonuclease 2 (APE2), uracil-DNA glycosylase

2 (UNG2), nth endonuclease III-like 1, methylpurine-DNA

glycosylase (MPG), human MutY homolog, and X-ray

repair cross-complementing protein 1 (XRCC1) [49]. It is

possible that PCNA functions as a bridge for BER proteins

and stimulates their activities and acts as a coordinator for

the repair process [67]. MMR amends misincorporated

bases, which can produce from small insertion/deletion

and polymerase error loops achieved during recombination

and replication. It also operates for the beginning stages of

damage recognition [74]. The repair machinery takes away

the error-comprising part of a freshly synthesized strand,

and repairs targets to the newly generated single-stranded

gap [47]. In MMR, PCNA is needed for repair synthesis and

the beginning stages of damage recognition. MMR needs to

discriminate between the original and newly synthesized

strand to function properly. Because PCNA is loaded onto

the DNA in the only possible orientation, facing the 3’-end

of the daughter strand, discrimination is possible. Indeed,

exonuclease excisions of incorrectly incorporated nucleotides

in the growing strand are carried out in the 5’-3’ direction.

PCNA interacts directly with Msh6 (MutS homolog 6),

Msh3 (MutS homolog 3), Mlh1 (MutL homolog 1), and

EXO1 (exonuclease 1). MLH1 possesses PIP-boxes, MSH3,

and MSH6 [65].

Post-Translational Modifications of PCNA

PCNA is modified by several post-translational modifications,

including ubiquitylation, sumoylation, acetylation, and

phosphorylation. PCNA was recently shown to be subject

to nitrosylation at specific cysteine residues for which the

biological significance remains to be determined [1, 26].

Post-translational modification of PCNA seems to be

important for the polymerase switch, with post-translational

modification by ubiquitin being the best known. Mono-

ubiquitiylation of PCNA at Lys164 is induced by Rad6 and

Rad18 in a DNA damage-dependent manner [29, 60, 64],

which serves as a signal for activation of the translesion

synthesis pathway [75]. It is achieved by consequent

movement of the ubiquitin-activating enzyme E1, specific

Fig. 2. DNA replication and repair.

(A) During DNA replication, replicative polymerases, including DNA

polymeraseδ (Polδ), are associated with PCNA and ensure progression

of the replication fork mediated by the MCM complex. (B) Upon

encountering a replication block such as DNA damage, PCNA

modified by ubiquitylation (Ub) plays a key role in recruiting

translesion synthesis DNA polymerases, including Polη, which

initiates damage bypass. PCNA exists as stable trimers that form a

closed ring with a hole in the center that encircles duplex DNA.

640 Park et al.


ubiquitin-conjugation enzyme E2 (which in humans might

be either Rad6A or Rad6B), and RING (really interesting

new gene) finger-containing E3 ubiquitin ligase (Rad18)

[26, 91]. Mono-ubiquitylation of PCNA directs a switch

between processive DNA polymerase and TLS DNA

polymerase and results in error-prone bypass replication

[47]. In addition, polyubiquitylation of PCNA at Lys164

and Lys63 needs the heterodimeric ubiquitin-conjugation

enzyme Ubc13-Mms2 and a specific RING-finger-containing

E3 ubiquitin ligase, Rad5 (in yeast) [75]. Rad5 promotes

PCNA polyubiquitylation via interactions with both

Ubc13-Mms2 and PCNA. In humans, Rad5 orthologs, SNF2

histone linker PHD RING helicase, helicase-like transcription

factor, and RING finger protein 8, have been found to be

catalyzed by Mm2-Ubc13-dependent polyubiquitylation of

PCNA [11, 76]. Another PCNA modification is sumoylation

on Lys164, and to a lesser portion, Lys127, by the E2 SUMO

conjugating enzyme Ubc9 combination with E3 SUMO

ligase Siz1. The crystal structures of mono-ubiquitylated,

polyubiquitylated, and sumolylated PCNA were solved

[17, 18] and they showed that the modified positions were

located on the backside of PCNA (Figs. 3A and 3B). PCNA

Fig. 3. PCNA modifications.

(A and B) Side view of SUMO- and ubiquitin-modified PCNA. The SUMO (orange) and ubiquitin (magenta) groups are located on the back of

PCNA (cyan). SUMO and ubiquitin are oriented differently relative to PCNA. Left, ribbon representation; middle, analogous space-filling

representation; right, molecular surface representation of the SUMO- and ubiquitin-modified PCNA. (C) Structure of a single SUMOPCNA subunit

superimposed with the structure of ubiquitin from UbiPCNA is shown. The PDB ID is 3PGE for the SUMO-modified PCNA and 3L10 for the

ubiquitin-modified PCNA.



sumoylation shows inhibition effects on the interaction of

PIP-box protein and PCNA. However, it has not yet been

characterized in mammals. Modification of PCNA by

ubiquitin and SUMO modulates the function of its target

protein by modifying, creating, or blocking the binding

motif. Both SUMO and ubiquitin are targeted to Lys164

residues of PCNA, and these modifications control the

various functions of PCNA [64]. In order to understand the

difference and similarity between post-translationally

modified forms of PCNA, the structures of UbiPCNA andSUMOPCNA were superimposed (Fig. 3C). Although these

modification positions coincide, the modifier positions are

quite different in both structures. UbiPCNA and SUMOPCNA

structures revealed that the ubiquitin and SUMO moieties

are located on the back face of the PCNA ring and interact

with the loop of PCNA via its hydrophobic surface [73].

The SUMO moiety is a more radial position than the

ubiquitin. This difference in modifier position is probably

caused by the longer flexible linker at the C-terminus of

ubiquitin in comparison with that of SUMO [11, 17].

Recently, new modifications of PCNA have been reported.

Aspartic acid and glutamic acid residues of PCNA undergo

esterification: methyl esterification on several aspartic

acids and glutamic acids residues. Interestingly, PCNA

methylation is associated with breast cancer and believed

to be cancer-specific [27]. Use of 2D-PAGE and a specifically

generated antibody revealed that an acidic isoform of

PCNA, cancer-specific PCNA (csPCNA), is exclusively

expressed in malignant tissues, including breast cancer,

prostate cancer, and esophageal adenocarcinoma, but not

in normal cells [82]. The functional results of these

modifications are not clearly known. The methyl esterification

of PCNA is likely to induce conformational changes in the

structure of PCNA, and it may facilitate or disrupt the

interaction with partner proteins. Therefore, PCNA has the

potential for use in the development of new cancer markers

and targeting of csPCNA in cancer cells.

PCNA in Cell Cycle and Apoptosis

PCNA-interacting proteins play major roles in the

regulation of the cell cycle. PCNA itself is a cyclin [49] that

is highly up-regulated during the S-phase and it binds to

cyclin-CDK complexes [86] as well as the CDK inhibitor,

p21 [21]. These interactions produce a PCNA-p21/CDK-

cyclin quaternary complex that could be independent from

the DNA replication machinery [89]. In the regulation of

cell cycle, p21 modulates critically the function of PCNA

[16]. p21Cip1/Waf1 is the main mediator of growth arrest

induced by p53 in response to DNA damage [13, 38, 69].

Tumor suppressor protein p21 having the PIP-box

modulates cell cycle progression by directly binding to

PCNA through its C-terminal region [48].

PCNA is involved in the regulation of damage-induced

apoptosis and programed cell death. The physical

interaction of PCNA with Gadd45 and MyD118 (myeloid

cell differentiation protein) has also been shown. They

have similar domains that mediate interaction of PCNA,

leading to negative cell growth [65, 77]. ING1 (inhibitor of

growth 1) is a tumor suppressor protein that binds PCNA

through the site used by growth regulatory proteins [70].

Specifically, the p33ING1 isoform of ING1 includes a PIP

domain that binds with PCNA [59]. Therefore, PCNA can

function as a bridging molecule that targets proteins with

distinct roles in DNA-based processes [39].

The PCNA structure has been conserved during evolution.

Human, rat, mouse, and Drosophila melanogaster PCNAs are

highly conserved in primary sequences [80]. The sequences

of full-length rat and human PCNAs are conserved, with

the exception of four amino acids (Fig. 4A). Human PCNA,

which consists of 261 amino acid residues, includes a

central hole used for interaction with DNA (Fig. 5) [21]. It is

composed of an N-terminal domain (amino acids 1-117), a

flexible IDCL (amino acids 118–135) and a C-terminal

domain (amino acids 136-261) (Fig. 4B). Crystallographic

study has shown that PCNA is composed of a toroid shape

structure in a head-to-tail manner [58]. The crystal structure

of yeast PCNA was determined and followed by the

human PCNA-p21 complex structure [88]. The structures

obtained from analysis of yeast, human, archaeal, and

plant PCNAs revealed similarities for the DNA polymerase

III β subunit [21, 36, 43, 66]. The DNA polymerase III β

subunit forms a homodimer with a six-fold symmetrical

ring, wherein each monomer consists of three repeating

domains [33]. Similarly, PCNA also exhibits a six-fold

symmetrical ring that encircles DNA. In contrast to the

two-subunit structure of DNA polymerase III β rings, most

of PCNA proteins have homotrimeric rings composed of

three PCNA homologs (PCNA1, PCNA2, and PCNA3)

(Fig. 6A). Head-to-tail arrangement of the three monomers

(29 kDa in human) gives rise to two distinct faces, the back

and front (C-terminus) [47, 67]. Each PCNA monomer

consists of two domains connected with an extended β-

sheet across the IDCL (Fig. 4A). PCNA monomers bind to

antiparallel interactions, resulting in six-fold symmetry

[26]. The PCNA ring has an overall negative charge with a

positively charged inner surface owing to the existence of

Lys and Arg [21]. The positively charged inner surface is

642 Park et al.


formed by α-helices interacted with the negatively charged

DNA backbone and the outer surface is composed of β-

sheets [45]. The PCNA monomer belongs to the α/β

protein family, which contains four α-helices and a twisted

β-sheet composed of 18 antiparallel β-strands (Fig. 4B) [51].

The interaction with partner proteins occurs on the front

side of PCNA where the IDCL is located. The back side of

PCNA is the site for post-translational modifications and

Fig. 4. Domain and secondary structures of PCNAs.

(A) Secondary structures of hPCNA, mPCNA, DmPCNA, and rPCNA. The secondary structure is shown according to the hPCNA structure.

Alpha helices are shown as rectangles and β-sheets as arrows. Loops are shown as black lines. Residues that are identical between the four species

are indicated blue-shadded Box. Sequence alignment was performed by ClustalW and Jalview. (B) Schematic diagram showing domains of the

full-length PCNA.

Fig. 5. Structure of PCNA bound to DNA.

PCNA-DNA model derived from PDB ID 3K4X. DNA forms a ~40° angle with the central axis of PCNA.



contains several loops [65, 71]. PCNA structures are known

to complex with DNA, proteins, and peptides [2, 6, 21, 57].

The complexes formed through binding of PCNA to DNA

and proteins/peptides have provided valuable insight into

the mechanism by which PCNA functions during DNA

processing.

PCNA Interaction with Partner Proteins

Interaction with PCNA-partner proteins is a key

regulatory role in various PCNA cellular functions. PCNA

interacts directly with many of the proteins involved in

various cellular processes [47]. Table 1 represents the major

PCNA-dependent activities and the respective PCNA-

binding proteins. The interaction sites of PCNA are shown

with its partner proteins in Fig. 6A. PCNA interacts with

partner proteins via the hydrophobic patch on its front-

facing side created by the IDCL (amino acids 118-135), the

central loop (amino acids 41-44), and the C-terminal tail

(amino acids 254-257) [15]. The ICDL is a major interaction

site for several proteins, including p21, Pol δ, MeCTr, DNA

ligase 1, and FEN1 [39]. The globular N-terminus including

α-helices is the interaction site with cyclin D, and the

extreme C-terminus is crucial for interactions with Polε,

RFC, CDK2, and Gadd45 [9]. Many PCNA-interacting

partners include a conserved PIP-box PCNA-binding motif,

Q-X-X-(L/M/I)-X-X-(F/Y)-(F/Y), and they are consisted of

hydrophobic and aromatic residues for interaction (Fig. 6C)

[83]. A general motif controlling PCNA-protein interactions

is marked in quite a few of the human proteins [47]. The

PIP motif forms a 310 helix that enters into the hydrophobic

groove in the PCNA (Fig. 6B) [2, 6]. Recent studies have

focused on PIP-box interaction and identification of an

additional modulation protein-protein interface. The crystal

structure of human PCNA-p21CIP1/WAF1 showed the typical

interaction of a PCNA-PIP box (PDB ID, 1AXC) [21].

Interestingly, the mutation of PCNA with extensive affinity

for PIP-box revealed the DNA replication defects and the

elevated plasticity of PCNA for partner protein affinities

[40]. Some PCNA-interacting proteins do not possess the

PIP-box sequence. Instead, a PCNA interaction motif, K-A-

(A/L/I)-(A/L/Q)-x-x-(L/V), mediates PCNA interactions

[39, 87]. However, some PCNA-binding proteins can

interact with PCNA independently of the classical PIP-box

or the KA-box through another binding site on PCNA [49].

For example, FEN1 utilizes the PIP-box motif and its

flanking sequences located at the extreme C-terminal tail,

as well as several additional contacts from its globular N-

terminal region, to interact with the C-terminus and IDCL

on PCNA [57]. Because a large number of PCNA partner

candidates by database search studies contain pathways

that are irrelevant to DNA replication, DNA repair, or

Fig. 6. Binding sites on PCNA interaction partners.

(A and B) PCNA interacts with protein partners through the frontal hydrophobic groove organized by the central loop (CL, amino acids 41-44,

colored purple), the C-terminal tail (CT, amino acids 254-257, colored magenta), and the interdomain-connecting loop (IDCL, amino acids 118-

135, colored orange). (C) PIP-box and p21 PIP-box motifs are shown.

644 Park et al.


chromatin assembly, the identification of these additional

bindings may announce new functions of PCNA [15].

Summary

PCNA plays crucial roles in DNA replication, DNA

repair, the cell cycle, and apoptosis, and it interacts

with many partner proteins to accomplish these roles.

Conversion of PCNA-binding proteins can be started by

phosphorylation, proteolysis, affinity competition, and

modification of PCNA by sumoylation and ubiquitylation.

PCNA function is controlled by interaction partners as well

as post-translational modifications of itself. Many PCNA

partner proteins include PIP-box motifs and their binding

modes are conserved. A hydrophobic groove at the front of

PCNA serves as a docking site for the consensus PIP-box

motifs. An interdomain-connecting loop on the front-facing

PCNA ring serves as a major interaction site. PCNA

expression relates to cell proliferation and it has diagnostic

value in many types of cancers. In addition, it is also a

target for cancer therapy and its inhibitors are currently

being developed as potential anticancer drugs. These

studies for the interaction with partner proteins, signaling

regulation, or trimer formation of PCNA can approach to

develop new therapeutic agents. Two types of PCNA-

targeting peptide agents have been reported and some

peptides disrupt protein interactions and others prevent

the phosphorylation of Tyr211. Functional activation of

PCNA may contribute to a favorable patient response and

provide a therapeutic tool to overcome the development of

resistance to other therapies. Structural and biochemical

studies of the PCNA protein may provide a model target

for designing therapeutic agents, as well as evaluating the

efficacy of anticancer drugs. Further studies are being

conducted to identify the complex structures in PCNA and

its partner proteins/compounds, as well as structure-based

regulation of PCNA.

Acknowledgments

This study was supported by the Basic Science Research

Program through the National Research Foundation of

Table 1. PCNA-binding proeteins.

Activities Proteins

DNA polymerases polη, polι, polλ, polδ, polβ, polε, polκ, polζ, Rev1

Flap-endonuclease FEN1

DNA ligase DNA ligase 1

Topoisomerase Topo Iiα

Poly (ADP-ribose) polymerase PARP-1

Helicases, ATPases Srs2, WRN, RECQ5, Mgs1, Rrm3

Protein kinase CDK2, EGF Receptor

Clamp loader Rfc1, Rfc3, Rfc4

Mismatch repair enzyme Msh3, Msh6, Mlh1, EXO1

Base excision repair enzymes NTH1, XRCC1, APE1, APE2, UNG2, MPG, Hmyh

Nucleotide excision repair enzyme XPG

Histone chaperone CAF-1

Histone acetyltransferase p300

Histone deacetyltransferase HDAC1

DNA methyltransferase DNMT1

Replication licensing factor Cdt1

Sister-chromatid cohesion factors Chl1, Eco1, Ctf18

Chromatin remodeling factor WSTF

Cell cycle regulators p21, p57, Cyclin D1

E3 ubiquitin ligases Rad5, Rad18

E2 SUMO-conjugating enzyme Ubc9

Apoptotic factor Gadd45, p53, ING1b

PIP-box seqence containing proteins indicated by a bold letter. The proteins are originated from mammals.



Korea (NRF) funded by the Ministry of Education, Science

and Technology (2014-046706) to S.B.J. This study was also

supported by the Research Fund Program of the Research

Institute for Basic Sciences, Pusan National University,

Korea, 2013 (Project No. RIBS-PNU-2013-203).

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Structural and Functional Insight into Proliferating Cell Nuclear Antigen