解密PCNA的多功能伴侣蛋白网络

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"PCNA众多合作伙伴之谜 - Emma Warbrick - 学术论文" 本文探讨了PCNA（增殖细胞核抗原）与多种蛋白质相互作用的领域，这是一片快速发展的科研前沿。PCNA在DNA复制和处理的多个环节中扮演关键角色，它作为一个滑动平台，能够介导蛋白质与DNA之间的互动。一个引人注目的发现是，许多蛋白质通过包含一个保守模体的小区域与PCNA结合，这些蛋白质涉及细胞周期调控以及DNA处理过程。模体的顺序和调节性结合到PCNA可能对DNA复制和修复期间事件的有序进行有所贡献。研究结果显示，这种模体与PCNA的交互结构基础在古细菌和古菌中就已经非常古老。通过对这些功能性模体如何在现今生物体的蛋白质中被招募的分析，我们得以了解这些复杂的系统是如何从原始生物进化而来的。作者Emma Warbrick在文章中指出，PCNA最初被识别时，因其在细胞周期中的重要作用而闻名，尤其是在DNA合成期间。它形成一个三聚体结构，环绕在DNA上，提供了一个稳定的支架，使多种参与复制和修复的酶可以定位并协同工作。文章进一步讨论了通过结构生物学和生物化学方法揭示的PCNA-蛋白质相互作用的细节。这些研究揭示了如何通过特定的氨基酸序列和构象，使得这些蛋白质能够识别并结合到PCNA的特定表面区域，即所谓的“PCNA交互界面”或“PCNA绑定盒”。此外，文章还强调了在DNA损伤响应中PCNA的重要性。当DNA受到损伤时，一些蛋白质会优先结合PCNA，启动修复机制，确保遗传信息的准确传递。这些动态的相互作用网络展示了生命体如何精细地协调其分子机器以应对不同生理条件下的挑战。 PCNA与多蛋白质的复杂相互作用网络是细胞维持基因稳定性、应对损伤和控制细胞周期的关键。理解这些相互作用有助于我们深入认识DNA复制和修复的分子机制，并为开发新的药物靶点和治疗策略提供了理论基础。

The puzzle of PCNA's many partners

Emma Warbrick

Summary

The identification of proteins that interact with proliferat-

ing cell nuclear antigen (PCNA) has recently been a

rapidly expanding field of discovery. PCNA is involved in

many aspects of DNA replication and processing, form-

ing a sliding platform that can mediate the interaction of

proteins with DNA. It is striking that many proteins bind to

PCNA through a small region containing a conserved

motif; these include proteins involved in cell cycle

regulation as well as those involved in DNA processing.

Sequential and regulated binding of motif-containing

proteins to PCNA may contribute to the ordering of events

during DNA replication and repair. Results from bacterio-

phages and archaea show that the structural basis for the

interaction of this motif with PCNA is extremely ancient.

The analysis of how such functional motifs have been

recruited to proteins in present day organisms helps us to

understand how these complex systems arose from

ancestral organisms. BioEssays 22:997±1006, 2000.

ß 2000 John Wiley & Sons, Inc.

Introduction

PCNA (proliferating cell nuclear antigen) was originally dis-

covered as an antigen found only in the nucleus of dividing

from which it derives its name.

(1)

It was independently iden-

tified as a protein with elevated levels during S phase of the cell

cycle.

(2)

A few years later, as a result of work to reconstitute

SV40-dependent replication in vitro, PCNA was identified as

an essential factor in DNA replication.

(3)

PCNA is now known

to be essential for the processivity of the DNA polymerase

complex, and also for the correct co-ordination of leading and

lagging strand synthesis.

(4)

Study of the crystal structure of

PCNA reveals a ring-shaped trimeric complex with striking

sixfold symmetry, which can encircle double-stranded DNA

and slide freely along it.

(5,6)

This structural information was

the vital clue to how PCNA could stably associate with DNA

without binding directly to it, and how it could link the poly-

merase complex to the DNA strand in a processive manner. It

is now known that, although PCNA has no endogenous enzy-

matic activity, it forms a sliding platform that can mediate the

interaction of several proteins with DNA in a non-sequence-

specific manner.

(7±9)

So-called ``sliding clamps'' are highly

conserved through evolution: homologues of PCNA are found

in eukaryotes, archaea, bacteriophages and some viruses.

The b-subunit of E. coli DNA polymerase III shares a very

similar three-dimensional structure with eukaryotic PCNA,

despite forming a dimeric, rather than trimeric, complex.

In the last few years, it has been shown that PCNA is

essential not only for DNA replication, but also for several

forms of DNA repair, including nucleotide excision repair

(NER), base excision repair (BER) and mismatch repair

(MMR).

(7,8)

More recently, a role for PCNA has been demon-

strated in various aspects of post-replicative processing, such

as cytosine methylation and chromatin assembly, although the

exact function of PCNA in these processes is not clear.

The identification of proteins that interact with PCNA has

been extensively studied recently.

(10)

As predicted, many

PCNA-interacting proteins are involved in various aspects of

DNA replication and processing, and hence these proteins are

probably using PCNA's ``sliding clamp'' properties to mediate

their interaction with DNA. It is intriguing, however, that cell

cycle regulatory proteins have also been found to interact with

PCNA. Such proteins, which include p21

WAF1/Cip1

, p57, cyclin

D, Gadd45 and Myd118 play multiple and, in many cases, not

completely understood, roles in the regulation of proliferation

and cell cycle progression. Although there is no clear evidence

yet, it seems likely that protein interactions with PCNA may be

a mechanism to co-ordinate DNA replication and repair with

the cell cycle.

One of the most interesting observations that has emerged

from the study of PCNA-binding proteins is that many contain

a conserved PCNA-binding motif (Table 1; Figure 1).

(11)

The PCNA-binding motif present in the regulatory protein p21

(also known as WAF1, Cip1, Sdi1 etc.) has been extensively

characterised, and its interactions with PCNA have been

mapped at the molecular level.

(6,12)

Biochemical evidence has

shown that other motif-containing proteins share a common

binding site on PCNA.

(13±17)

Although each PCNA trimer

theoretically has the capacity to interact with three such

proteins, the large number of motif-containing proteins far

exceeds this capacity, suggesting that the interactions of these

proteins with PCNA must be regulated. As described above,

this motif is also found in regulatory molecules, such as p21,

which have roles in regulating proliferation and in DNA

BioEssays 22:997±1006, ß 2000 John Wiley & Sons, Inc. BioEssays 22.11 997

Department of Surgery and Molecular Oncology, University of

Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY,

UK. E-mail: e.warbrick@dundee.ac.uk

Funding agency: The Association for International Cancer Research.

Abbreviations: ATP, adenosine triphosphate; BER, base excision

repair; CDK, cyclin-dependent kinase; CKII, casein kinase II; DNA

Mtase, DNA cytosine 5-methyltransferase; MMR, mismatch repair;

NER, nucleotide excision repair; PCNA, proliferating cell nuclear

antigen; RFC, replication factor C; RPA, replication protein A; UDG,

uracil DNA glycosylase.

Review articles

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