Chk1 and Claspin potentiate PCNA ubiquitination

Yang, Xiaohong; Shiotani, Bunsyo; Classon, Marie; Zou, Lee

doi:10.1101/gad.1632808

Cited by 100 publications

(103 citation statements)

References 35 publications

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“…Given this previous evidence, we thought that the kinase-independent role of Chk1 in DNA replication after UV irradiation might depend on Claspin. We used previously described siRNA for Claspin (14). In agreement with previous reports (29,30), Claspin down-regulation reduced the rate of fork elongation during unperturbed DNA replication (Fig.…”

Section: Effect Of Chk1 In Replication Fork Progression and Specializsupporting

confidence: 71%

“…Interestingly, not only Chk1 but also Claspin potentiates PCNA ubiquitination after UV irradiation (100 J/m 2 ) (14). Under our experimental settings, although Chk1 affects polη/ PCNA interaction and polη focal organization, neither Chk1 nor Claspin affect PCNA ubiquitination (Fig.…”

Section: Discussionmentioning

confidence: 59%

“…Claspin is a mediator of the checkpoint response in S phase that promotes Chk1 stabilization and activation (26)(27)(28). Interestingly, Claspin stabilizes replication forks independently of Chk1 phosphorylation (29), and Claspin and Chk1 were shown to positively regulate PCNA ubiquitination (14). Given this previous evidence, we thought that the kinase-independent role of Chk1 in DNA replication after UV irradiation might depend on Claspin.…”

Section: Effect Of Chk1 In Replication Fork Progression and Specializmentioning

confidence: 77%

“…Scorah and colleagues discovered a proliferating cell nuclear antigen (PCNA) binding motif of Chk1 (Chk1_TRFF motif) required for the efficient dissociation of Chk1 from chromatin after UV irradiation (13). Yang et al also reported a kinase-independent function of Chk1 in the control of UV-induced PCNA ubiquitination (14). This modification of PCNA is known for its contribution to the activation of the DNA replication auxiliary process translesion DNA synthesis (TLS), which triggers the utilization of specialized polymerases (pols) to overcome fork stalling by using DNA lesions as replication templates (15).…”

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confidence: 99%

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Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA

Speroni

Federico

Mansilla

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The checkpoint kinases Chk1 and ATR are broadly known for their role in the response to the accumulation of damaged DNA. Because Chk1 activation requires its phosphorylation by ATR, it is expected that ATR or Chk1 down-regulation should cause similar alterations in the signals triggered by DNA lesions. Intriguingly, we found that Chk1, but not ATR, promotes the progression of replication forks after UV irradiation. Strikingly, this role of Chk1 is independent of its kinase-domain and of its partnership with Claspin. Instead, we demonstrate that the ability of Chk1 to promote replication fork progression on damaged DNA templates relies on its recently identified proliferating cell nuclear antigen-interacting motif, which is required for its release from chromatin after DNA damage. Also supporting the importance of Chk1 release, a histone H2B-Chk1 chimera, which is permanently immobilized in chromatin, is unable to promote the replication of damaged DNA. Moreover, inefficient chromatin dissociation of Chk1 impairs the efficient recruitment of the specialized DNA polymerase η (pol η) to replication-associated foci after UV. Given the critical role of pol η during translesion DNA synthesis (TLS), these findings unveil an unforeseen facet of the regulation by Chk1 of DNA replication. This kinase-independent role of Chk1 is exclusively associated to the maintenance of active replication forks after UV irradiation in a manner in which Chk1 release prompts TLS to avoid replication stalling. T he checkpoint kinases ATR and Chk1 are central factors in the DNA damage response (1). During the S phase checkpoint, ATR is activated at single-stranded DNA (ssDNA) and this event, in turn, activates the effector kinase Chk1. Although ATR remains associated with the DNA, activated Chk1 rapidly spreads throughout the whole nucleus. Within the nucleoplasm, Chk1 delays the progression through S phase via phosphorylation of key target genes (2, 3).Several lines of evidence suggest that the activities of ATR and Chk1 are also required for proper unperturbed S phase progression. In fact, ATR or Chk1 loss leads to embryonic lethality (4-7), and Chk1 heterozygosity is associated with multiple defects, including a miscoordinated cell cycle and increased apoptosis (8).A contribution of Chk1 to replication fork stability during unperturbed DNA replication was identified and characterized in detail (9-11). Chk1 activity promotes the maintenance of global replication rates by regulating origin firing. In line with these observations, the monoallelic expression of the mutant Chk1 S317A, which is not phosphorylated by ATR, impairs fork elongation (12). Together, these results reveal an unambiguous role of the Chk1 kinase during unperturbed DNA replication. Intriguingly, recent reports described a kinase-independent effect of Chk1 on DNA replication-associated events. Scorah and colleagues discovered a proliferating cell nuclear antigen (PCNA) binding motif of Chk1 (Chk1_TRFF motif) required for the efficient dissociation of Chk1 from chromatin a...

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Section: Effect Of Chk1 In Replication Fork Progression and Specializsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 59%

Section: Effect Of Chk1 In Replication Fork Progression and Specializmentioning

confidence: 77%

mentioning

confidence: 99%

See 2 more Smart Citations

Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA

Speroni

Federico

Mansilla

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…For example, more mammalian factors have been identified as regulating the monoubiquitination of PCNA, including p21, p53, PTIP/Swift, Chk1, Claspin, Timeless, and Tipin (14). Furthermore, Zou and coworkers have shown that Claspin can regulate the chromatin binding of Rad18 while Chk1 indirectly regulates the monoubiquitination of PCNA by stabilizing the protein level of Claspin (37). How Claspin regulates the recruitment of Rad18 is not known; however, an interaction between Claspin and the RPA heterotrimer has been reported (38).…”

Section: Discussionmentioning

confidence: 99%

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Tian

Sharma

Zou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer gene 1 ( BRCA1 ) deficient cells not only are hypersensitive to double-strand breaks but also are hypersensitive to UV irradiation and other agents that cause replication blockade; however, the molecular mechanisms behind these latter sensitivities are largely unknown. Here, we report that BRCA1 promotes cell survival by directly regulating the DNA damage tolerance pathway in response to agents that create cross-links in DNA. We show that BRCA1 not only promotes efficient mono- and polyubiquitination of proliferating cell nuclear antigen (PCNA) by regulating the recruitment of replication protein A, Rad18, and helicase-like transcription factor to chromatin but also directly recruits translesion polymerases, such as Polymerase eta and Rev1, to the lesions through protein–protein interactions. Our data suggest that BRCA1 plays a critical role in promoting translesion DNA synthesis as well as DNA template switching.

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Regulation of translesion DNA synthesis in mammalian cells

Tang

Guo

2020

Environ and Mol Mutagen

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The genomes of all living cells are under endogenous and exogenous attacks every day, causing diverse genomic lesions. Most of the lesions can be timely repaired by multiple DNA repair pathways. However, some may persist during S‐phase, block DNA replication, and challenge genome integrity. Eukaryotic cells have evolved DNA damage tolerance (DDT) to mitigate the lethal effects of arrested DNA replication without prior removal of the offending DNA damage. As one important mode of DDT, translesion DNA synthesis (TLS) utilizes multiple low‐fidelity DNA polymerases to incorporate nucleotides opposite DNA lesions to maintain genome integrity. Three different mechanisms have been proposed to regulate the polymerase switching between high‐fidelity DNA polymerases in the replicative machinery and one or more specialized enzymes. Additionally, it is known that proliferating cell nuclear antigen (PCNA) mono‐ubiquitination is essential for optimal TLS. Given its error‐prone property, TLS is closely associated with spontaneous and drug‐induced mutations in cells, which can potentially lead to tumorigenesis and chemotherapy resistance. Therefore, TLS process must be tightly modulated to avoid unwanted mutagenesis. In this review, we will focus on polymerase switching and PCNA mono‐ubiquitination, the two key events in TLS pathway in mammalian cells, and summarize current understandings of regulation of TLS process at the levels of protein–protein interactions, post‐translational modifications as well as transcription and noncoding RNAs. Environ. Mol. Mutagen. 61:680–692, 2020. © 2020 Wiley Periodicals, Inc.

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Chk1 and Claspin potentiate PCNA ubiquitination

Cited by 100 publications

References 35 publications

Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA

Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Regulation of translesion DNA synthesis in mammalian cells

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