DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1

Cobb, Jennifer A.

doi:10.1093/emboj/cdg391

Cited by 310 publications

(344 citation statements)

References 55 publications

(102 reference statements)

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“…3A,B). Consistent with previous data, ChIP experiments in cells synchronized by ␣-factor and released into HU demonstrated that Pol -HA was enriched at early origins (Aparicio et al 1999;Cobb et al 2003;Katou et al 2003;Lucca et al 2004). As expected, Pol -HA was not enriched in wild-type cells at sequences 14 kb from ARS607 or 8 kb from the ARS 305, indicating that HU had stalled forks before they reached distal positions.…”

Section: Stalled Replisomes Are Unstable In Asf1⌬ Cellssupporting

confidence: 90%

“…The S-phase checkpoint allows cells to survive in the presence of replication stress by maintaining the stability of replisome proteins at stalled replication forks (Cobb et al 2003;Katou et al 2003;Tercero et al 2003;Lucca et al 2004). Because asf1⌬ cells display spontaneous DNA damage phenotypes (see introduction), and because Asf1 is required to complete DNA synthesis in the presence of DNA damage (Fig.…”

Section: Stalled Replisomes Are Unstable In Asf1⌬ Cellsmentioning

confidence: 99%

“…The S-phase checkpoint promotes survival in the presence of DNA damage by maintaining the integrity of stalled replication forks (Desany et al 1998), stabilizing DNA replication proteins at stalled forks (Cobb et al 2003;Katou et al 2003;Lucca et al 2004), and preventing the generation of aberrant DNA structures that can lead to chromosomal Asf1 promotes replication fork stability rearrangements (Lopes et al 2001;Tercero and Diffley 2001;Sogo et al 2002;Tercero et al 2003). Upon deletion of the protein kinases Mec1 and Tel1 required for sensing DNA damage, Pol ␣, Pol , and Mcm4 are all lost from stalled forks (Katou et al 2003); likewise, a mutant allele of Mec1 alone has been shown to reduce DNA Pol association (Cobb et al 2003). Thus, although checkpoint signaling appears crucial for fork stability, Pol ␣ had not been observed to behave differently from other DNA polymerases previously.…”

Section: Changes In Stalled Replisome Architecture In the Absence Of mentioning

confidence: 99%

“…ChIP assays were performed essentially as described (StrahlBolsinger et al 1997;Cobb et al 2003), with details provided in the Supplemental Material.…”

Section: Chipmentioning

confidence: 99%

“…In mec1 cells, these changes include loss of Cdc45 and polymerase (Pol ) from chromatin (Cobb et al 2003;Katou et al 2003). In rad53⌬ cells, losses of DNA polymerases ␣, ␦, and from stalled forks have been reported (Lucca et al 2004).…”

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confidence: 99%

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Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C

Franco¹,

Lam²,

Burgers³

et al. 2005

Genes Dev.

128

125

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Chromatin assembly and DNA replication are temporally coupled, and DNA replication in the absence of histone synthesis causes inviability. Here we demonstrate that chromatin assembly factor Asf1 also affects DNA replication. In budding yeast cells lacking Asf1, the amounts of several DNA replication proteins, including replication factor C (RFC), proliferating cell nuclear antigen (PCNA), and DNA polymerase (Pol ), are reduced at stalled replication forks. In contrast, DNA polymerase ␣ (Pol ␣) accumulates to higher than normal levels at stalled forks in asf1⌬ cells. Using purified, recombinant proteins, we demonstrate that RFC directly binds Asf1 and can recruit Asf1 to DNA molecules in vitro. We conclude that histone chaperone protein Asf1 maintains a subset of replication elongation factors at stalled replication forks and directly interacts with the replication machinery.[Keywords: Chromatin assembly; histone deposition; DNA replication; genome stability] Supplemental material is available at http://www.genesdev.org. In eukaryotes, DNA is assembled into a nucleoprotein complex called chromatin. The fundamental repeating unit of chromatin is the nucleosome, which consists of 146 bp of DNA wrapped around an octamer of core histone proteins, comprised of two H2A/H2B dimers flanking an inner (H3/H4) 2 tetramer. In vivo, histone deposition can occur by DNA replication-coupled or replication-independent mechanisms (for review, see Franco and Kaufman 2004). In either case, histone deposition is mediated by specialized assembly proteins. The best characterized replication-coupled chromatin assembly factor is chromatin assembly factor-1 (CAF-1), an evolutionarily conserved protein complex that binds histone H3 and H4 and delivers them to replicating DNA through an interaction with proliferating cell nuclear antigen (PCNA), the DNA polymerase processivity protein (for review, see Asf1, another evolutionarily conserved histone chaperone, functions during both replication-coupled and replication-independent chromatin assembly. Asf1 bound to histones H3/H4 stimulates histone deposition by CAF-1 in vitro (Tyler et al. 1999;Sharp et al. 2001), and Asf1 physically interacts with the p60/Cac2 subunit of CAF-1 (Tyler et al. 2001;Krawitz et al. 2002;Mello et al. 2002). In yeast, Asf1 and the Hir proteins directly interact and function together to promote heterochromatic gene silencing (Kaufman et al. 1998;Sharp et al. 2001;Sutton et al. 2001;Krawitz et al. 2002). Consistent with a role in multiple deposition pathways, Asf1 copurifies with both CAF-1 and Hir protein complexes in human cell extracts (Tagami et al. 2004).Asf1 also contributes to genome stability during S phase in a manner distinct from both CAF-1 and the Hir proteins. Unlike yeast cells lacking CAF-1 or Hir proteins, cells lacking Asf1 are sensitive to the DNA synthesis inhibitor hydroxyurea (HU) and the DNA topoisomerase I inhibitor camptothecin (CPT), and display synthetic genetic interactions with DNA synthesis genes including the initiation/elongation factor C...

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Section: Stalled Replisomes Are Unstable In Asf1⌬ Cellssupporting

confidence: 90%

Section: Stalled Replisomes Are Unstable In Asf1⌬ Cellsmentioning

confidence: 99%

Section: Changes In Stalled Replisome Architecture In the Absence Of mentioning

confidence: 99%

“…ChIP assays were performed essentially as described (StrahlBolsinger et al 1997;Cobb et al 2003), with details provided in the Supplemental Material.…”

Section: Chipmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C

Franco¹,

Lam²,

Burgers³

et al. 2005

Genes Dev.

128

125

View full text Add to dashboard Cite

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Recombinational DNA repair is regulated by compartmentalization of DNA lesions at the nuclear pore complex

Géli

Lisby

2015

BioEssays

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The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of "difficult to repair" lesions such as double-strand breaks without a repair template and eroded telomeres in telomerase-deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure-forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC-facilitated repair.

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RMI1 attenuates tumor development and is essential for early embryonic survival

Chen

You²,

Jiang

et al. 2010

Mol. Carcinog.

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RMI1/BLAP75 (RecQ-Mediated Genome Instability 1/Bloom Associated protein 75) is an OB-fold protein highly conserved from yeast to human. Previous studies showed that RMI1 is required for the stability of the BLM/RMI1/TopIIIα complex and for the suppression of elevated sister chromatids exchange (SCE). The presence of RMI1 strongly stimulates the Holliday dissolution activity of the Bloom helicase in vitro. The in vivo function of RMI1, however, remains largely undefined. To address this question, we generated RMI1 knockout mice through homologous replacement targeting. We found that, while RMI1+/− mice showed no obvious developmental phenotype, deletion of both mRMI1 alleles resulted in early embryonic lethality before implantation. To determine whether RMI1 plays a role in tumorigenesis, we generated RMI1/p53 double heterozygous mice and analyzed their onset of ionizing radiation-induced tumor development. RMI1+/−/p53+/− mice succumbed to tumor with a higher frequency and exhibited a substantially shortened survival when compared to the wild type, RMI1+/− and p53+/− cohorts. These results demonstrated a dual-role of RMI1 in embryonic development and tumor suppression.

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DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1

Cited by 310 publications

References 55 publications

Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C

Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C

Recombinational DNA repair is regulated by compartmentalization of DNA lesions at the nuclear pore complex

RMI1 attenuates tumor development and is essential for early embryonic survival

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