Mechanisms and regulation of DNA end resection

Longhese, Maria Pia; Bonetti, Diego; Manfrini, Nicola; Clerici, Michela

doi:10.1038/emboj.2010.165

Cited by 91 publications

(162 citation statements)

References 122 publications

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“…Resection comprises the 59-to-39 nucleolytic processing of DNA ends by the MRN complex (Rupnik et al 2010) in conjunction with auxiliary factors including CtIP, RECQ family helicases, and the nucleases Exo1 and Dna2 (Zou and Elledge 2003;Bernstein and Rothstein 2009;Mimitou and Symington 2009;Huertas 2010;Longhese et al 2010;You and Bailis 2010). Resulting ssDNA overhangs are then coated by the ssDNA-binding complex RPA (replication protein A) before being substituted by RAD51 proteins with the help of factors such as RAD51 paralogs, RAD52, and other proteins that comprise the FA (Fanconi anemia) pathway such as FANCD1 (FA-associated nuclease CD1)/BRCA2 (breast cancer-2, early onset) and FANCN/PALB2 (partner and localizer of Mazon et al 2010).…”

Section: Cellular Responses To Dna Strand Breaksmentioning

confidence: 99%

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Polo¹,

Jackson²

2011

Genes Dev.

978

946

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Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.

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Section: Cellular Responses To Dna Strand Breaksmentioning

confidence: 99%

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Polo¹,

Jackson²

2011

Genes Dev.

978

946

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“…To further characterize the genetic requirements for Mte1 focus formation, we tested factors involved in DNA repair and telomere maintenance: Rad52, the major recombination mediator in yeast (for review, see Symington et al 2014), and Mre11, a component of the Mre11-Rad50-Xrs2 complex involved in the initial recognition and short-range resection of DSBs and in telomere length maintenance (Goudsouzian et al 2006;Sabourin et al 2007;Longhese et al 2010). In both the rad52Δ and mre11Δ cells, we observed an increase in both spontaneous and MMS-induced Mte1 foci (Supplemental Fig.…”

Section: Defective Hr and Telomere Dysfunction Induce Mte1 Focus Formmentioning

confidence: 99%

Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance

et al. 2016

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Mph1 is a member of the conserved FANCM family of DNA motor proteins that play key roles in genome maintenance processes underlying Fanconi anemia, a cancer predisposition syndrome in humans. Here, we identify Mte1 as a novel interactor of the Mph1 helicase in Saccharomyces cerevisiae. In vitro, Mte1 (Mph1-associated telomere maintenance protein 1) binds directly to DNA with a preference for branched molecules such as D loops and fork structures. In addition, Mte1 stimulates the helicase and fork regression activities of Mph1 while inhibiting the ability of Mph1 to dissociate recombination intermediates. Deletion of MTE1 reduces crossover recombination and suppresses the sensitivity of mph1Δ mutant cells to replication stress. Mph1 and Mte1 interdependently colocalize at DNA damage-induced foci and dysfunctional telomeres, and MTE1 deletion results in elongated telomeres. Taken together, our data indicate that Mte1 plays a role in regulation of crossover recombination, response to replication stress, and telomere maintenance.

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“…Cyclin-dependent kinase (Cdk1 in S. cerevisiae) activity is required for this telomeric C-strand resection (17, 49), which occurs only during S and G 2 cell cycle phases, when Cdk1 activity is high and telomeres are elongated by telomerase (36). The MRX (Mre11-Rad50-Xrs2) complex and Sae2 have been shown to be important for resection of telomeric ends, with MRX playing the major role (8,14,28,31). Moreover, Exo1 and Sgs1-Dna2 can provide a backup mechanism for telomere resection when Sae2-MRX activity is compromised (8).…”

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confidence: 99%

A Balance between Tel1 and Rif2 Activities Regulates Nucleolytic Processing and Elongation at Telomeres

et al. 2012

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Generation of G-strand overhangs at Saccharomyces cerevisiae yeast telomeres depends primarily on the MRX (Mre11-Rad50-Xrs2) complex, which is also necessary to maintain telomere length by recruiting the Tel1 kinase. MRX physically interacts with Rif2, which inhibits both resection and elongation of telomeres. We provide evidence that regulation of telomere processing and elongation relies on a balance between Tel1 and Rif2 activities. Tel1 regulates telomere nucleolytic processing by promoting MRX activity. In fact, the lack of Tel1 impairs MRX-dependent telomere resection, which is instead enhanced by the Tel1-hy909 mutant variant, which causes telomerase-dependent telomere overelongation. The Tel1-hy909 variant is more robustly associated than wild-type Tel1 to double-strand-break (DSB) ends carrying telomeric repeat sequences. Furthermore, it increases the persistence at a DSB adjacent to telomeric repeats of both MRX and Est1, which in turn likely account for the increased telomere resection and elongation in TEL1-hy909 cells. Strikingly, Rif2 is unable to negatively regulate processing and lengthening at TEL1-hy909 telomeres, indicating that the Tel1-hy909 variant overcomes the inhibitory activity exerted by Rif2 on MRX. Altogether, these findings highlight a primary role of Tel1 in overcoming Rif2-dependent negative regulation of MRX activity in telomere resection and elongation.A highly ordered nucleoprotein complex called the telomere prevents the ends of linear chromosomes from being recognized as DNA double-strand breaks (DSBs) (reviewed in reference 30). Another key function of telomeres is to compensate for the incomplete replication of chromosome ends caused by discontinuous DNA synthesis. In most eukaryotes, telomeric DNA comprises tandemly repeated G-rich sequences (TG 1-3 repeats in Saccharomyces cerevisiae yeast and T 2 AG 3 in vertebrates), ending in a single-stranded 3= overhang (G tail) (reviewed in reference 20). The addition of telomeric repeats depends on the action of telomerase, a specialized reverse transcriptase that extends the TGrich strand of chromosome ends (23). The yeast telomerase complex consists of a reverse transcriptase subunit (Est2), a template RNA (TLC1), and two accessory proteins (Est1 and Est3), which are required for telomerase activity in vivo but not in vitro.The single-stranded G tails of budding yeast telomeres are short (about 10 to 15 nucleotides [nt]) for most of the cell cycle, but their length increases transiently to 50 to 100 nucleotides in late S phase (15, 50). While telomeric G tails can be generated during lagging-strand replication by removal of the last RNA primer, the 5= C strand of the telomere generated by leadingstrand synthesis must be nucleolytically processed (resected) to generate 3= overhangs (32, 51). Cyclin-dependent kinase (Cdk1 in S. cerevisiae) activity is required for this telomeric C-strand resection (17, 49), which occurs only during S and G 2 cell cycle phases, when Cdk1 activity is high and telomeres are elongated by telomerase (36...

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Mechanisms and regulation of DNA end resection

Cited by 91 publications

References 122 publications

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance

A Balance between Tel1 and Rif2 Activities Regulates Nucleolytic Processing and Elongation at Telomeres

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