The DNA replication checkpoint response stabilizes stalled replication forks

Lopes, Massimo; Cotta‐Ramusino, Cecilia; Pellicioli, Achille; Liberi, Giordano; Plevani, Paolo; Muzi-Falconi, Marco; Newlon, Carol S.; Foiani, Marco

doi:10.1038/35087613

Cited by 705 publications

(728 citation statements)

References 28 publications

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“…Mec1, the yeast ATR homolog, is essential for stabilization of stalled replication forks (Lopes et al, 2001;Tercero and Diffley, 2001). In mammalian cells, ATR was shown to be important in preventing DSB formation at stalled replication forks (Brown and Baltimore, 2003).…”

Section: Discussionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

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Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

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Section: Discussionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

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“…Cells experiencing replication stress activate checkpoint pathways, which in budding yeast have been shown to stabilize stalled replication forks 1,5 . In general, much less is known about the processing of stalled replication forks in mammalian cells.…”

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confidence: 99%

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

et al. 2013

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The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA doublestrand breaks.

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“…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).…”

Section: Changes In Stalled Replisome Architecture In the Absence Ofmentioning

confidence: 99%

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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The DNA replication checkpoint response stabilizes stalled replication forks

Cited by 705 publications

References 28 publications

Interplay between ATM and ATR in the regulation of common fragile site stability

Interplay between ATM and ATR in the regulation of common fragile site stability

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

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

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