The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Winczura, Alicja; Appanah, Rowin; Tatham, Michael H.; Hay, Ronald T.; Piccoli, Gaicomo De

doi:10.1371/journal.pgen.1008427

Cited by 14 publications

(15 citation statements)

References 118 publications

(126 reference statements)

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“…Studies in Drosophila , budding yeast, and fission yeast have implied that aberrancies in SMC5/6 complex functions can result in the upregulation of a CHEK2 kinase-mediated DDR ( Ampatzidou et al, 2006 ; Pebernard et al, 2008b ; Torres-Rosell et al, 2005 ; Tran et al, 2016 ; Winczura et al, 2019 ). We reasoned that if NPC apoptosis in Smc5 cKO brain is mediated by CHEK2 signaling pathway, Chek2 knockout would rescue the reduced cortex size in Smc5 cKO mice.…”

Section: Resultsmentioning

confidence: 99%

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

Atkins

et al. 2020

eLife

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Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein Smc5 is conditionally knocked out (cKO) in the developing neocortex. Smc5 cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. Smc5 cKO NPCs formed DNA bridges during mitosis and underwent chromosome missegregation. SMC5/6 depletion triggers a CHEK2-p53 DNA damage response, as concomitant deletion of the Trp53 tumor suppressor or Chek2 DNA damage checkpoint kinase rescued Smc5 cKO neurodevelopmental defects. Further assessment using Smc5 cKO and auxin-inducible degron systems demonstrated that absence of SMC5/6 leads to DNA replication stress at late-replicating regions such as pericentromeric heterochromatin regions. In summary, SMC5/6 is important for completion of DNA replication prior to entering mitosis, which ensures accurate chromosome segregation. Thus, SMC5/6 functions are critical in highly proliferative stem cells during organism development.

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Section: Resultsmentioning

confidence: 99%

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

Atkins

et al. 2020

eLife

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“…A detailed enzymatic characterization of the Pol ε REL synthesis defect will distinguish among these possibilities in the future. In addition, it will be interesting to determine how POPS functions are regulated by sumoylation, which was recently reported to occur in this region 44,45 .…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase ε relies on a unique domain for efficient replisome assembly and strand synthesis

et al. 2020

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DNA polymerase epsilon (Pol ε) is required for genome duplication and tumor suppression. It supports both replisome assembly and leading strand synthesis; however, the underlying mechanisms remain to be elucidated. Here we report that a conserved domain within the Pol ε catalytic core influences both of these replication steps in budding yeast. Modeling cancerassociated mutations in this domain reveals its unexpected effect on incorporating Pol ε into the four-member pre-loading complex during replisome assembly. In addition, genetic and biochemical data suggest that the examined domain supports Pol ε catalytic activity and symmetric movement of replication forks. Contrary to previously characterized Pol ε cancer variants, the examined mutants cause genome hyper-rearrangement rather than hypermutation. Our work thus suggests a role of the Pol ε catalytic core in replisome formation, a reliance of Pol ε strand synthesis on a unique domain, and a potential tumor-suppressive effect of Pol ε in curbing genome rearrangements .

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“…Proteomic analyses of chromatin under replication have revealed that DNA replication forks are embedded in a SUMO-rich environment [81][82][83]. Although the exact functions of replisome SUMOylation remain to be elucidated, a recent report showed that the SUMOylation of the catalytic subunit of DNA polymerase ε is important for DNA replication in yeast [64,65]. In addition to the SUMOylation of specific factors, we have proposed that the collective SUMOylation of the replication machinery supports DNA replication by creating an environment that facilitates interactions among replication factors [84], analogous to the SUMO-based group modification model proposed by Stefan Jentsch for DNA repair [85].…”

Section: Sumo and Ubiquitin In Dna Replicationmentioning

confidence: 99%

Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1

Galarreta

Valledor

Fernández-Capetillo

et al. 2021

IJMS

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Post-translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitin-mediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage.

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The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Cited by 14 publications

References 118 publications

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

DNA polymerase ε relies on a unique domain for efficient replisome assembly and strand synthesis

Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1

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