Exo1 Roles for Repair of DNA Double-Strand Breaks and Meiotic Crossing Over in<i>Saccharomyces cerevisiae</i>

Tsubouchi, Hideo; Ogawa, Hideyuki

doi:10.1091/mbc.11.7.2221

Cited by 202 publications

(204 citation statements)

References 66 publications

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“…Candidates for such activity are the nucleases Exo1 and Dna2 and the helicase Sgs1, which all contribute to resect DSB and chromosome ends in mitotic S. cerevisiae cells (21)(22)(23)(24). Consistent with this hypothesis, EXO1 deletion has been shown to impair repair of meiotic DSBs and to reduce meiotic crossing over (25).…”

mentioning

confidence: 61%

Processing of Meiotic DNA Double Strand Breaks Requires Cyclin-dependent Kinase and Multiple Nucleases

Manfrini

Guerini²,

Citterio

et al. 2010

Journal of Biological Chemistry

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Meiotic recombination requires the formation of programmed Spo11-dependent DNA double strand breaks (DSBs). In Saccharomyces cerevisiae, the Sae2 protein and the Mre11-Rad50-Xrs2 complex are necessary to remove the covalently attached Spo11 protein from the DNA ends, which are then resected by so far unknown nucleases. Here, we demonstrate that phosphorylation of Sae2 Ser-267 by cyclin-dependent kinase 1 (Cdk1) is required to initiate meiotic DSB resection by allowing Spo11 removal from DSB ends. This finding suggests that Cdk1 activity is required for the processing of Spo11-induced DSBs, thus providing a mechanism for coordinating DSB resection with progression through meiotic prophase. Furthermore, the helicase Sgs1 and the nucleases Exo1 and Dna2 participate in lengthening the 5-3 resection tracts during meiosis by controlling a step subsequent to Spo11 removal.During the first meiotic division, homologous maternal and paternal chromosomes are segregated. In most organisms, homologs must be physically connected to ensure their proper segregation (1). By virtue of cohesion between sister chromatids, the exchange of chromosome arms through chiasmata formation provides the physical connections between homologous chromosomes. Chiasmata are generated by recombination events, which are initiated by the formation of selfinflicted DNA double strand breaks (DSBs).3 DSB formation requires meiosis-specific gene products, including the evolutionary conserved topoisomerase-like enzyme Spo11, as well as the three components of the MRX complex (Mre11-Rad50-Xrs2) (2). In particular, a Spo11 dimer coordinately breaks both DNA strands, creating a DSB with covalent linkages between the 5Ј DNA ends and the catalytic tyrosine residue of each Spo11 monomer (3). Then, Spo11 must be removed by endonucleolytic cleavage to allow further DSB end processing by 5Ј-3Ј resection that is required to initiate homologous recombination (4). This event is promoted by the Sae2 protein and the MRX complex, which are required to catalyze the endonucleolytic removal of Spo11-linked oligonucleotides (3,5,6). In fact, budding yeast sae2⌬ cells and rad50s separation-of-function mutants allow DSB formation but are totally defective in Spo11 removal from DSB ends (3,5,(7)(8)(9). Similarly, mre11 alleles impairing Mre11 nuclease activity allow Spo11-induced DSB formation, but not Spo11 removal (10 -12), suggesting that the latter may take place by Mre11-catalyzed endonucleolytic cleavage and that Sae2 participates in this process. As recently shown, also Sae2 exhibits an endonuclease activity (13), suggesting that this protein, possibly in cooperation with MRX, may allow Spo11 removal by mediating an endonucleolytic cleavage close to the DNA end.Because DSBs are highly hazardous for genome stability, commitment to DSB resection and meiotic progression must be tightly regulated to ensure proper DSB repair. In vegetative Saccharomyces cerevisiae cells, DSB resection is promoted by the activity of the cyclin-dependent protein kinase Cdk1 (Cdc28/Clb) during...

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mentioning

confidence: 61%

Processing of Meiotic DNA Double Strand Breaks Requires Cyclin-dependent Kinase and Multiple Nucleases

Manfrini

Guerini²,

Citterio

et al. 2010

Journal of Biological Chemistry

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“…Usually, inactivation of Mre11 leads to increased sensitivity to MMS (3,7,20,22,53), although this is not always the case when the NBS1 component of the human M/R complex is mutated (54). Nonetheless, the sensitivity of the trypanosome null mutant to phleomycin and its altered integration patterns do show that Mre11 is involved in repair and recombination.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Mre11 Does Not Affect VSG Gene Duplication Mediated by Homologous Recombination in Trypanosoma brucei

Robinson¹,

McCulloch²,

Conway

et al. 2002

Journal of Biological Chemistry

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We demonstrate, by gene deletion analysis, that Mre11 has a critical role in maintaining genomic integrity in Trypanosoma brucei. mre11 ؊/؊ null mutant strains exhibited retarded growth but no delay or disruption of cell cycle progression. They showed also a weak hyporecombination phenotype and the accumulation of gross chromosomal rearrangements, which did not involve sequence translocation, telomere loss, or formation of new telomeres. The trypanosome mre11 ؊/؊ strains were hypersensitive to phleomycin, a mutagen causing DNA double strand breaks (DSBs) but, in contrast to mre11 ؊/؊ null mutants in other organisms and T. brucei rad51 ؊/؊ null mutants, displayed no hypersensitivity to methyl methanesulfonate, which causes point mutations and DSBs. Mre11 therefore is important for the repair of chromosomal damage and DSBs in trypanosomes, although in this organism the intersection of repair pathways appears to differ from that in other organisms. Mre11 inactivation appears not to affect VSG gene switching during antigenic variation of a laboratory strain, which is perhaps surprising given the importance of homologous recombination during this process.

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“…There are some reports that loss of EXO1 gives rise to one form of the MMR-deficient syndrome human nonpolyposis colon cancer, HNPCC (Wu et al 2001), but a direct association has been questioned (Thompson et al 2004). Eukaryotic EXO1 is involved in various DNA metabolic pathways other than MMR, including meiosis (Fiorentini et al 1997) and recombination (Tsubouchi and Ogawa 2000). EXO1 may also play a role in resecting ends at broken replication forks to prevent generation of recombinogenic intermediates.…”

Section: Replication Fidelity Is Enhanced Through Nucleases Acting Inmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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Exo1 Roles for Repair of DNA Double-Strand Breaks and Meiotic Crossing Over inSaccharomyces cerevisiae

Cited by 202 publications

References 66 publications

Processing of Meiotic DNA Double Strand Breaks Requires Cyclin-dependent Kinase and Multiple Nucleases

Processing of Meiotic DNA Double Strand Breaks Requires Cyclin-dependent Kinase and Multiple Nucleases

Inactivation of Mre11 Does Not Affect VSG Gene Duplication Mediated by Homologous Recombination in Trypanosoma brucei

The role of DNA exonucleases in protecting genome stability and their impact on ageing

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