Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA

Leung, Wendy; Baxley, Ryan M.; Moldovan, George‐Lucian; Bielinsky, Anja‐Katrin

doi:10.3390/genes10010010

Cited by 71 publications

(46 citation statements)

References 234 publications

(308 reference statements)

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“…Posttranslational modifications of PCNA, including sumoylation, are known to regulate the choice between DNA damage repair or tolerance (Leung et al, 2018). To address the role of PCNA sumoylation in Top1cc processing, we analyzed the pol30-2KR mutant (lysines K127 and K164 are mutated to arginines), which lacks detectable sumoylation (Davies and Ulrich, 2012).…”

Section: Sumoylation Changes In Ulp1-dn and Siz2dmentioning

confidence: 99%

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Serbyn

Bagdiul

Michel

et al. 2020

Preprint

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Several endogenous metabolites, environmental agents, and therapeutic drugs promote formation of covalent DNA-protein crosslinks (DPCs). Persistent DPCs pose a serious threat to genome integrity and are eliminated by multiple repair pathways. Aberrant Top1 crosslinks to DNA, or Top1ccs, are processed by Tdp1 and Wss1 functioning in parallel pathways in Saccharomyces cerevisiae. It remains obscure how cells choose between these diverse mechanisms of DPC repair. Here we show that several SUMO biogenesis factors -Ulp1, Siz2, Slx5, Slx8 -control repair of Top1cc or an analogous DPC lesion. Genetic analysis reveals that SUMO promotes Top1cc processing in the absence of Tdp1 but has an inhibitory role if cells additionally lack Wss1. In the tdp1D wss1D mutant, the E3 SUMO ligase Siz2 stimulates sumoylation in the vicinity of the DPC, but not SUMO conjugation to Top1. This Siz2-dependent sumoylation delays DPC repair when cells progress through S and G2 phases.Our findings suggest that SUMO tunes available repair pathways to facilitate faithful DPC repair.

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Section: Sumoylation Changes In Ulp1-dn and Siz2dmentioning

confidence: 99%

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Serbyn

Bagdiul

Michel

et al. 2020

Preprint

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“…Contradicting results should be considered to arrive at definitive conclusions, even when it is difficult to specify the reasons for the contradictions. For the details on the subsequent molecular mechanisms of TLS and HDR, on the significance of ubiquitination on different sites in PCNA, and on other modifications of PCNA, see the excellent recent reviews (Branzei and Psakhye 2016;Cipolla et al 2016;Garcia-Rodriguez et al 2016;Livneh et al 2016;Branzei and Szakal 2017;Kanao and Masutani 2017;Poole and Cortez 2017;Vaisman and Woodgate 2017;Leung et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Masuda

Masutani

2019

Critical Reviews in Biochemistry and Molecular Biology

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DNA is constantly exposed to a wide variety of exogenous and endogenous agents, and most DNA lesions inhibit DNA synthesis. To cope with such problems during replication, cells have molecular mechanisms to resume DNA synthesis in the presence of DNA lesions, which are known as DNA damage tolerance (DDT) pathways. The concept of ubiquitination-mediated regulation of DDT pathways in eukaryotes was established via genetic studies in the yeast Saccharomyces cerevisiae, in which two branches of the DDT pathway are regulated via ubiquitination of proliferating cell nuclear antigen (PCNA): translesion DNA synthesis (TLS) and homology-dependent repair (HDR), which are stimulated by mono-and polyubiquitination of PCNA, respectively. Over the subsequent nearly two decades, significant progress has been made in understanding the mechanisms that regulate DDT pathways in other eukaryotes. Importantly, TLS is intrinsically error-prone because of the miscoding nature of most damaged nucleotides and inaccurate replication of undamaged templates by TLS polymerases (pols), whereas HDR is theoretically error-free because the DNA synthesis is thought to be predominantly performed by pol d, an accurate replicative DNA pol, using the undamaged sister chromatid as its template. Thus, the regulation of the choice between the TLS and HDR pathways is critical to determine the appropriate biological outcomes caused by DNA damage. In this review, we summarize our current understanding of the species-specific regulatory mechanisms of PCNA ubiquitination and how cells choose between TLS and HDR. We then provide a hypothetical model for the spatiotemporal regulation of DDT pathways in human cells.

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“…During DNA synthesis, PCNA interacts with the replicative polymerases on each strand and enhances their processivities, rendering PCNA essential for DNA replication and cellular proliferation (Choe and Moldovan, 2017;Leung et al, 2018). On the lagging strand PCNA also recruits and coordinates the activity of the Flap endonuclease (FEN1) which cleaves the RNA primer displaced by Polδ, and DNA ligase 1 (LIG1) which seals the resulting nick to complete OF maturation (OFM) (Zheng and Shen, 2011).…”

Section: Introductionmentioning

confidence: 99%

PCNA ubiquitination protects stalled replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly

Thakar

Leung

Nicolae

et al. 2019

Preprint

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Upon genotoxic stress, PCNA ubiquitination allows for replication of damaged DNA by recruiting lesion-bypass DNA polymerases. However, PCNA is also ubiquitinated during normal S-phase progression. By employing ubiquitination-deficient 293T and RPE1 cells generated through CRISPR/Cas9 genome editing, we show that this modification promotes cellular proliferation and suppression of genomic instability under normal growth conditions. Loss of PCNA-ubiquitination results in DNA2-mediated but MRE11independent nucleolytic degradation of nascent DNA at stalled replication forks. This degradation is linked to defective gap-filling in the wake of the replication fork, and incomplete Okazaki fragment synthesis and maturation, thus interfering with efficient PCNA unloading by ATAD5 and subsequent nucleosomal deposition by CAF-1.Moreover, concomitant loss of PCNA-ubiquitination and BRCA2 results in a synergistic increase in nascent DNA degradation and sensitivity to PARP-inhibitors. In conclusion, we show that by ensuring efficient Okazaki fragment maturation, PCNA-ubiquitination protects fork integrity and promotes the resistance of BRCA-deficient cells to PARPinhibitors.

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Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA

Cited by 71 publications

References 234 publications

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

PCNA ubiquitination protects stalled replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly

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