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Review
. 2011 Sep 16;585(18):2780-5.
doi: 10.1016/j.febslet.2011.05.053. Epub 2011 Jun 1.

Dynamic regulation of PCNA ubiquitylation/deubiquitylation

Jennifer T Fox  1 , Kyoo-young Lee, Kyungjae Myung
Affiliations
Review

Dynamic regulation of PCNA ubiquitylation/deubiquitylation

Jennifer T Fox et al. FEBS Lett. .

Abstract

Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation plays a crucial role in maintaining genomic stability during DNA replication. DNA damage stalling the DNA replication fork induces PCNA ubiquitylation that activates DNA damage bypass to prevent the collapse of DNA replication forks that could potentially produce double-strand breaks and chromosomal rearrangements. PCNA ubiquitylation dictates the mode of bypass depending on the level of ubiquitylation; monoubiquitylation and polyubiquitylation activate error-prone translesion synthesis and error-free template switching, respectively VSports手机版. Due to the error-prone nature of DNA damage bypass, PCNA ubiquitylation needs to be tightly regulated. Here, we review the molecular mechanisms to remove ubiquitin from PCNA including the emerging role of USP1 and ELG1 in this fascinating process. .

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Figures

Figure 1
Figure 1
PCNA modifications occur following DNA replication stress. In response to DNA damage stalling the DNA replication fork, K164 of PCNA can either be SUMOylated (SUMO) by Ubc9/Siz1 or monoubiquitylated (Ub) by Rad6/Rad18. The former modification inhibits inappropriate homologous recombination by recruiting the helicase Srs2, and the latter attracts specialized polymerases that carry out translesion synthesis. K164 monoubiquitylation can also be further extended by Ubc13/Mms2/Rad5 to initiate template switching by a currently unknown mechanism. PCNA SUMOylation and ubiquitylation are both reversible – SUMO is removed by ULP1 and ubiquitin is removed by USP1/ELG1.
Figure 2
Figure 2
A model for the role of ELG1 in PCNA deubiquitylation. Upon encountering DNA damage, the replication machinery becomes stalled. PCNA is then monoubiquitylated, and a TLS polymerase is recruited to the damage site to replace the replicative polymerase (Polδ/ε) and bypass the lesion. Once bypass has occurred, ELG1, which becomes concentrated at stalled forks with distinct foci structures in the nucleus, binds to PCNA and recruits the USP1/UAF1 complex. USP1 deubiquitylates PCNA, displacing the TLS polymerase and allowing Polδ/ε to resume normal replication.
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References

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