Mcm10 interacts with Rad4/Cut5TopBP1 and its association with origins of DNA replication is dependent on Rad4/Cut5TopBP1

Taylor, Mark; Moore, Karen; Murray, Johanne M.; Aves, Stephen J.; Price, C P

doi:10.1016/j.dnarep.2011.09.001

Cited by 19 publications

(21 citation statements)

References 55 publications

(95 reference statements)

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“…Besides its essential role during replication initiation, Mcm10 is also required for DNA elongation and has been identified at replication forks by chromatin immunoprecipitation [5, 37]. Because Mcm10 interacts with the Mcm2-7 complex as well as Pol-α [2, 5, 18–20, 30, 32–34, 38], it was proposed to link DNA unwinding and DNA synthesis [5].…”

Section: Structure and Function Of Mcm10mentioning

confidence: 99%

MCM10: One tool for all—Integrity, maintenance and damage control

Thu

Bielinsky

2014

Seminars in Cell & Developmental Biology

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Minichromsome maintenance protein 10 (Mcm10) is an essential replication factor that is required for the activation of the Cdc45:Mcm2-7:GINS helicase. Mcm10's ability to bind both ds and ssDNA appears vital for this function. In addition, Mcm10 interacts with multiple players at the replication fork, including DNA polymerase-α and proliferating cell nuclear antigen with which it cooperates during DNA elongation. Mcm10 lacks enzymatic function, but instead provides the replication apparatus with an oligomeric scaffold that likely acts in the coordination of DNA unwinding and DNA synthesis. Not surprisingly, loss of Mcm10 engages checkpoint, DNA repair and SUMO-dependent rescue pathways that collectively counteract replication stress and chromosome breakage. Here, we review Mcm10's structure and function and explain how it contributes to the maintenance of genome integrity.

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Section: Structure and Function Of Mcm10mentioning

confidence: 99%

MCM10: One tool for all—Integrity, maintenance and damage control

Thu

Bielinsky

2014

Seminars in Cell & Developmental Biology

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“…Mcm10 was first identified in S. cerevisiae as a gene required for DNA replication 2,3 . Studies in different organisms from yeast to humans have shown that Mcm10 can interact with several replication initiation factors including Mcm2-7, 2,4-10 Cdc45, 11-13 TopBP1 14 and RecQ4 15-17 …”

Section: Introductionmentioning

confidence: 99%

Xenopus Mcm10 is a CDK-substrate required for replication fork stability

et al. 2016

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During S phase, following activation of the S phase CDKs and the DBF4-dependent kinases (DDK), double hexamers of Mcm2-7 at licensed replication origins are activated to form the core replicative helicase. Mcm10 is one of several proteins that have been implicated from work in yeasts to play a role in forming a mature replisome during the initiation process. Mcm10 has also been proposed to play a role in promoting replisome stability after initiation has taken place. The role of Mcm10 is particularly unclear in metazoans, where conflicting data has been presented. Here, we investigate the role and regulation of Mcm10 in Xenopus egg extracts. We show that Xenopus Mcm10 is recruited to chromatin late in the process of replication initiation and this requires prior action of DDKs and CDKs. We also provide evidence that Mcm10 is a CDK substrate but does not need to be phosphorylated in order to associate with chromatin. We show that in extracts depleted of more than 99% of Mcm10, the bulk of DNA replication still occurs, suggesting that Mcm10 is not required for the process of replication initiation. However, in extracts depleted of Mcm10, the replication fork elongation rate is reduced. Furthermore, the absence of Mcm10 or its phosphorylation by CDK results in instability of replisome proteins on DNA, which is particularly important under conditions of replication stress.

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“…31 In addition, Mcm10 travels with the replication fork, pointing to a function in DNA elongation. 28,[32][33][34] Although roles for Mcm10 in origin unwinding, elongation and pol-α regulation are not mutually exclusive, the notion that Mcm10 is part of the eukaryotic replisome is a matter of ongoing debate in the field. 15,[18][19][20] Here, we exploited the fact that PCNA ubiquitination and DRIM can be utilized as a sensitive biological readout for the accumulation of ssDNA gaps.…”

Section: Introductionmentioning

confidence: 99%

Mcm10 deficiency causes defective-replisome-induced mutagenesis and a dependency on error-free postreplicative repair

et al. 2014

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Mcm10 is a multifunctional replication factor with reported roles in origin activation, polymerase loading, and replication fork progression. the literature supporting these variable roles is controversial, and it has been debated whether Mcm10 has an active role in elongation. Here, we provide evidence that the mcm10-1 allele confers alterations in DNA synthesis that lead to defective-replisome-induced mutagenesis (DRIM). Specifically, we observed that mcm10-1 cells exhibited elevated levels of pCNA ubiquitination and activation of the translesion polymerase, pol-ζ. Whereas translesion synthesis had no measurable impact on viability, mcm10-1 mutants also engaged in error-free postreplicative repair (pRR), and this pathway promoted survival at semi-permissive conditions. Replication gaps in mcm10-1 were likely caused by elongation defects, as dbf4-1 mutants, which are compromised for origin activation did not display any hallmarks of replication stress. Furthermore, we demonstrate that deficiencies in priming, induced by a pol1-1 mutation, also resulted in DRIM, but not in error-free pRR. Similar to mcm10-1 mutants, DRIM did not rescue the replication defect in pol1-1 cells. thus, it appears that DRIM is not proficient to fill replication gaps in pol1-1 and mcm10-1 mutants. Moreover, the ability to correctly prime nascent DNA may be a crucial prerequisite to initiate error-free pRR.

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Mcm10 interacts with Rad4/Cut5TopBP1 and its association with origins of DNA replication is dependent on Rad4/Cut5TopBP1

Cited by 19 publications

References 55 publications

MCM10: One tool for all—Integrity, maintenance and damage control

MCM10: One tool for all—Integrity, maintenance and damage control

Xenopus Mcm10 is a CDK-substrate required for replication fork stability

Mcm10 deficiency causes defective-replisome-induced mutagenesis and a dependency on error-free postreplicative repair

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