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(The FASEB Journal. 2006;20:833-837.)
© 2006 FASEB

The fellowship of the rings: distinct pools of proliferating cell nuclear antigen trimer at work

Ennio Prosperi1

Istituto di Genetica Molecolare del CNR, sez. Istochimica e Citometria, Dipartimento di Biologia Animale, Università di Pavia, Pavia, Italy

1Correspondence: Istituto di Genetica Molecolare del CNR, sez. Istochimica e Citometria, Dipartimento di Biologia Animale, Università di Pavia, Piazza Botta, 10, Pavia 27100, Italy. E-mail: prosperi{at}igm.cnr.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PCNA-interacting proteins may be...
 Effect of PCNA binding...
 Regulation of PCNA multiple...
 CONCLUSIONS
 REFERENCES
 
The proliferating cell nuclear antigen (PCNA) is a homotrimeric ring-shaped protein that, by encircling DNA, may function as a sliding platform for proteins participating in various DNA transactions. PCNA plays a fundamental role in DNA replication and repair, but also in postreplicative events, like DNA methylation, chromatin assembly and remodeling, sister chromatid cohesion, and coordinates these activities with cell cycle control. However, relevant aspects of PCNA function are still not well understood, like the role of PCNA in the association with partner proteins, and how multiple protein interactions are orchestrated. Based on emerging evidence, I suggest that 1) PCNA interacting proteins may be reclassified in three major categories, namely, a) cell cycle control; b) DNA replication/repair; c) chromatin regulation/transcription. 2) PCNA is a negative regulator, rather than a processivity/recruitment factor, of chromatin-modifying enzymes. 3) At DNA replication sites, PCNA function may be envisaged with a model of "dynamic hand-off" of interacting partners that rapidly and transiently exchange in a mutually exclusive manner, while cyclin-dependent kinase (Cdk) 2 (CDK2) is stably bound to PCNA. The partner exchange might occur through a conformational change of the PCNA/protein/DNA complex allowing CDK2 to phosphorylate the partner protein, thereby enabling its hand-off from PCNA.—Prosperi, E. The fellowship of the rings: distinct pools of proliferating cell nuclear antigen trimer at work.


Key Words: proliferating cell nuclear antigen • DNA replication • DNA repair • CDK2 • chromatin-modifying enzymes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PCNA-interacting proteins may be...
 Effect of PCNA binding...
 Regulation of PCNA multiple...
 CONCLUSIONS
 REFERENCES
 
DURING S PHASE, each cell has to accomplish several important tasks required not only to replicate with high fidelity the genetic information, but also for proper organization and transmission of the genetic material to daughter cells.

Proliferating cell nuclear antigen (PCNA) plays a central role in DNA metabolism by providing a platform facilitating DNA binding, thereby conferring spatio-temporal specificity to the activity of proteins involved in various DNA transactions (1 ,2) . PCNA is a ring-shaped protein that may encircle DNA, thus functioning as a sliding clamp (3) . In this way, PCNA enhances the processivity of both replicative and translesion synthesis DNA polymerases (pols), and stimulates the catalytic activity of other enzymes involved in DNA replication and repair (4) . In addition, PCNA interacts with proteins participating in postreplicative processes like chromatin assembly and remodeling, as well as sister chromatid cohesion (4) , and couples these pathways with cell cycle control (5 ,6) . Recent reports have provided evidence that PCNA interacts also with proteins involved in transcriptional and chromatin structure regulation, thus linking these processes to the above pathways (7 , 8) .

To date, the number of PCNA-interacting proteins has increased considerably, and new possible candidates for interaction have been also suggested (9) , leading to further complexity to the PCNA roles.

PCNA has a structure formed by three identical monomers, thereby potentially allowing binding of multiple proteins to the same trimer (10) . In addition, PCNA exists both in a nucleoplasmic free and in a chromatin-bound state (5) , adding another level of complexity to understand whether different functions or interactions are related to a specific state. Thus, the ability of PCNA to orchestrate multiple protein associations remains to be clarified. In this review, some recent advances that may help to elucidate these aspects are presented, and a new model of PCNA functioning at DNA replication sites is proposed.


   PCNA-interacting proteins may be reclassified into three major classes
TOP
 ABSTRACT
 INTRODUCTION
 PCNA-interacting proteins may be...
Effect of PCNA binding...
 Regulation of PCNA multiple...
 CONCLUSIONS
 REFERENCES
 
Most PCNA-interacting proteins share a conserved stretch of 8 amino acids Qxxhxxaa, where h is a moderately hydrophobic residue (L, M, or I), and aa are two aromatic residues (FF or FY) (10) . This sequence, first identified in the Cdk inhibitor p21CDKN1A, has been termed PCNA-interacting protein (PIP) box (10) . Structural studies have shown that proteins interact with PCNA by positioning this short sequence into a hydrophobic pocket of the PCNA molecule formed by the interdomain connecting loop (IDCL) and by a hydrophobic patch proximal to this region (11 , 12) . However, not all PCNA-interacting proteins have a canonical PIP box, and binding to PCNA may occur even in its absence, as found for proteins like the histone acetyl transferase (HAT) p300, and histone deacetylase 1 (HDAC1) (7 ,13) . The PIP-related sequence QLxLF has been proposed to mediate interaction for DNA replication proteins in eubacteria, and to be partly conserved in proteins of higher organisms, like the chromatin assembly factor 1 (CAF-1), pol ß, or the p50 subunit of pol {delta} (14) . A shorter sequence, referred to as the KA motif, has also been suggested to mediate PCNA interaction with various replicative proteins (15) . Weak binding afforded by sequences resembling the PIP box may provide high overall affinity of a multimeric protein (16) , as it occurs for p50 and p125 subunits of pol {delta} holoenzyme (14 , 15) . In addition, a canonical PIP box present on the third subunit p66 (17) , may provide a structural link between the other subunits and PCNA (18) . A recent database search for potential PCNA interactors, based on the presence of a canonical PIP box, or a related sequence, has identified a number of new potential candidates (9) . Some of them belong to pathways distant from DNA replication, and thus require further testing to validate a true PCNA interaction.

PCNA-interacting proteins have been previously divided into groups according to their role in pathways like cell cycle, DNA replication/repair, chromatin remodeling, and apoptosis (2 , 4) . While a role of PCNA in the first two pathways appears to be established, the involvement in processes like apoptosis is less clear. I propose that PCNA-interacting protein may be reclassified only into three main categories, i.e., 1) cell cycle control; 2) DNA replication/repair, and 3) chromatin/transcription (Table 1 ). In the first group are cyclins, cyclin-dependent kinases (CDK), cell cycle-related phosphatase (CDC25C), and CDK inhibitors. In the second one, canonical and translesion synthesis DNA polymerases are present together with replication and repair endonucleases, DNA glycosylases, DNA ligase I (Lig I), and DNA helicases (for a list of proteins in these groups, see refs 2 and 4 ). A third group of proteins, involved in pathways described more recently but genetically discovered years ago (19) , includes the chromatin-assembly factor CAF-1, necessary to nucleosome reassembly, and the proteins Ctf7 and Ctf18 involved in sister chromatid cohesion, also required during DNA replication (2 ,4) ; the chromatin-modifying enzymes, whose activity is not restricted to S phase, like DNA methyltransferase 1 (DNMT1), HDAC1, p300, and poly(ADP-ribose) polymerase 1 (PARP-1) (7 , 13 , 20 , 21) ; finally, transcription factors that play an essential role in chromatin structure regulation, like the William syndrome transcription factor, Y-box binding protein 1, and retinoic acid receptor {alpha} (RAR{alpha}) (8 , 22 , 23) .


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  		Table 1. Classification of proteins interacting with PCNAa

PCNA-interacting proteins previously classified as apoptosis-related factors, have been subsequently found to participate in other pathways. As an example, p33ING1b protein (produced by a tumor suppressor gene), which was reported to protect from apoptosis after DNA damage (24) , has been recently shown to associate with two other PCNA interacting proteins, DNMT1 and HDAC1, to form a chromatin-modifying protein complex (25) . Thus, p33ING1b has been suggested to participate in a chromatin-remodeling pathway during DNA repair (24) . Other PCNA-interacting proteins involved in negative growth control after DNA damage, like GADD45, MyD118, and CR6, were also related to an apoptotic pathway (2 ,4) . However, other lines of evidence have suggested an involvement of GADD45 in chromatin accessibility (26) , and an interaction of GADD45 with p33ING1b has been also described (24) . Thus, it appears that the putative role for PCNA in apoptosis could be in fact mediated by a direct role in chromatin structure regulation.


   Effect of PCNA binding on partner activity
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 INTRODUCTION
 PCNA-interacting proteins may be...
 Effect of PCNA binding...
Regulation of PCNA multiple...
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Most proteins interacting with PCNA possess a catalytic activity, which is stimulated by PCNA, typically because of a processivity/recruitment effect increasing the residence time of a protein onto DNA, as it occurs for DNA polymerases (3 ,4) . In the case of flap endonuclease 1 (FEN1), PCNA appears to enhance catalytic activity by properly orienting the enzyme onto DNA substrate (27) . However, not all the enzymes interacting with PCNA are stimulated on binding. In fact, PCNA does not significantly stimulate the activity of DNA glycosylase NTH1, though stimulating that of MPG glycosylase (28 , 29) . Remarkably, the activity of some protein is actually inhibited, as demonstrated by in vitro and in vivo studies (Table 2 ). The first to be described has been terminal deoxynucleotidyltransferase (TDT), an enzyme catalyzing the addition of nucleotides to immunoglobulin (Ig) coding sequences during V(D)J recombination. TDT has been found to interact with PCNA through a region in the catalytic domain of the protein with the consequence that TDT activity is greatly inhibited by binding to PCNA (30) . Interestingly, TDT has been found to associate with a chromatin remodeling protein, TdIF2, and both proteins interact with PCNA (31) . More recently, PCNA has been shown to inhibit HAT activity of p300 in vitro, and to promote transcriptional repression in vivo (32) . PCNA has been found to inhibit also the activity of PARP-1 (21) , an important enzyme catalyzing the addition of multiple (ADP-ribose) units to protein substrates involved in DNA metabolism (33) . The activity of PARP-1 is likely to be inhibited through PCNA binding to the catalytic site, where a putative PIP sequence is located (21) . Both p300 and PARP-1 are involved in chromatin modification, since protein acetylation, and poly(ADP)-ribosylation are known to regulate chromatin structure, thereby influencing important processes like DNA replication, repair and transcription (13 , 33) . In particular, both acetylation and poly(ADP)-ribosylation have been found to inhibit enzymatic activity of base excision repair (BER) factors, like pol ß, and FEN1 (13 ,34) , known to interact with, and to be stimulated by PCNA. These findings suggest that PCNA may counteract negative posttranslational modifications induced by p300 and PARP-1. Altogether, these lines of evidence suggest that PCNA plays an important role in the negative regulation of chromatin modification processes.


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  		Table 2. Effect of PCNA binding on enzyme activitiesa


   Regulation of PCNA multiple associations: the preassembled replisome vs. the dynamic hand-off model
TOP
 ABSTRACT
 INTRODUCTION
 PCNA-interacting proteins may be...
 Effect of PCNA binding...
 Regulation of PCNA multiple...
CONCLUSIONS
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Due to the high number of proteins associating with PCNA, each interaction must be tightly coordinated in order to achieve a precisely ordered execution of PCNA-mediated DNA transactions. Two views on how this task is accomplished may be envisaged. The "replisome" or "synthesome" model suggests that DNA replication machinery exists as a stably preassembled multiprotein complex (4) . In this model, regulation of multiple interactions has been assumed to occur on the basis of the different binding affinity that each PCNA partner shows in respect of other competing proteins (4) . The possibility that three different proteins (i.e., a pol, FEN1, and Lig I) may bind the same trimer has been suggested for Sulfolobus sulfataricus PCNA (35) . However, a scenario with multiple proteins bound to the same PCNA trimer would complicate the task of choosing the right partner at the right moment, and increase steric hindrance of bound proteins. In fact, the crystal structure of human Lig I bound to PCNA has revealed an extensive interaction excluding other proteins from the complex (36) . The intriguing proposal that PCNA may exist as a double trimer (37 , 38) , adds DNA orientation problems to the regulation of multiple interactions.

More recently, the "dynamic hand-off" model has been proposed from studies on the orchestration of sequential events involving the 32 kDa subunit of replication protein A (RPA2), during DNA recombination and repair (16) . This model suggests a continuous ordered assembly and disassembly of complex structures on the basis of competitive association and dissociation (hand-off) reactions of proteins binding to RPA2 (39) . In a similar view, the "passing the baton" model proposed for BER, suggests that every step provides the substrate for binding the next partner (40) .

Can the hand-off model also be applied to PCNA? On the basis of recent results obtained from in vivo studies using green or red fluorescent proteins (GFP, RFP), the answer is positive. GFP- or RFP-tagged PCNA has been shown to be successfully recruited to DNA replication foci and to reside in these structures with a relatively little turn-over (41) . In contrast, the association of two PCNA binding proteins, Lig I and FEN1, has been found to be rapid and transient, indicating de novo loading at every Okazaki fragment (42 ,43) . These results have suggested that PCNA rings loaded onto DNA are recycled for multiple rounds of Okazaki fragment maturation, while PCNA binding proteins are not stable components of a multifunctional replication complex (43) . An indirect confirmation of this model has been provided by another study showing that PCNA trimers loaded onto DNA (chromatin-bound fraction) may be isolated as distinct pools containing selectively different partners, like DNA pol {delta} (p125 subunit) and Lig I (44) . These proteins have been found to interact with PCNA in a mutually exclusive manner, thus supporting the indication that PCNA partners are not present together as a large DNA replication complex. In contrast, CDK2 was consistently found in a complex containing PCNA associated either with pol {delta} or Lig I, or even in their absence (Fig. 1 ). CDK2 was not displaced by p21CDKN1A in vitro nor in vivo (44 45 46) , thus indicating that binding to PCNA does not overlap the IDCL region occupied by other proteins (45) . These data suggest a model of lagging strand DNA synthesis in which replication proteins temporarily associate and dissociate from PCNA platform (43) , to perform their relevant function (i.e., polymerization, flap removal and ligation), while CDK2 remains stably bound to the trimer. Although the presence of CDK2 at DNA replication foci was reported several years ago (47) , its role has remained unclear. Many PCNA-interacting proteins are targeted for CDK2-driven phosphorylation, including DNA pol {delta} (p125 and p66 subunits), FEN1, Lig I, as well as the large subunit (p145) of RFC (45) . The principal consequence of their phosphorylation is the loss of interaction with PCNA and a reduction in enzymatic activity (45) . Thus, in lagging strand DNA synthesis CDK2 might mediate hand-off of a PCNA partner by phosphorylating it after its specific reaction has been completed. How this task may be accomplished? Recent evidence obtained from crystallographic studies on FEN1 (48) , and also on Lig I (36) , have suggested that a conformational change (kink) in the FEN1-PCNA-DNA, or Lig I-PCNA-DNA complex, occurs on binding of the DNA intermediate, thereby catalyzing the reaction. This change might occur during the transition from "locked" inactive to "tethered" active state, shown for proteins interacting with E. coli clamp ß-protein (27 ,49) . The movement, termed rotary hand-off (48) , might then bring in contact the protein present at the IDCL of PCNA (e.g., FEN1, or Lig I) with the catalytic site of CDK2 bound to the same PCNA trimer, thereby triggering phosphorylation and consequent release of the interacting protein (Fig. 2 ). This sequence of events would help in PCNA clearance after each interaction, thus leaving a PCNA trimer available for binding the next partner.


Figure 1
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  		Figure 1. Mutual exclusion of PCNA-interacting proteins. During lagging strand synthesis, PCNA loaded onto DNA may be found in distinct pools in which a unique protein is bound to a trimer in the presence of CDK2. Two examples are depicted "freezing" transient complexes containing pol {delta} (for simplicity, only p125, p66, and p50 subunits), or Lig I. In the transition from a complex to another, a PCNA ring is temporarily left free of replication proteins, while CDK2 remains stably bound.


Figure 2
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  		Figure 2. Model showing dynamic hand-off of a PCNA-interacting protein. The schematic representation shows FEN1 binding to and dissociation from PCNA in three steps: (I) a locked-down inactive state; (II) an active conformation tethered to, and distorting DNA, to allow catalysis of the flap and concomitant phosphorylation by CDK2; (III) dissociation (hand-off) step from PCNA complex after phosphorylation. Note that for simplicity, cyclin A has not been drawn.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PCNA-interacting proteins may be...
 Effect of PCNA binding...
 Regulation of PCNA multiple...
 CONCLUSIONS
REFERENCES
 
PCNA trimers shift from a free nucleoplasmic to a chromatin-bound state. Distinct pools of PCNA may act in concert to accomplish different roles within the same pathway, as for instance negative regulation of protein modification to promote DNA repair. In lagging strand DNA synthesis, CDK2 may help PCNA to orchestrate multiple associations with a dynamic hand-off reaction, as suggested by the consequence of phosphorylation of PCNA-interacting proteins, and by the structure they adopt when tethered with the clamp onto DNA.


   ACKNOWLEDGMENTS
 
I wish to thank my collaborators Lucia A. Stivala, Ornella Cazzalini, Monica Savio, and Paola Perucca for experimental support, and particularly, A. Ivana Scovassi, for critical reading of the manuscript. Work in the author’s lab is supported by CNR and MIUR (FIRB Project RBNE0132MY).

Received for publication November 23, 2005. Accepted for publication January 3, 2006.


   REFERENCES
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 INTRODUCTION
 PCNA-interacting proteins may be...
 Effect of PCNA binding...
 Regulation of PCNA multiple...
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