Chromosome Fragmentation after Induction of a Double-Strand Break Is an Active Process Prevented by the RMX Repair Complex

Lobachev, Kirill S.; Vitriol, Eric A.; Stemple, Jennifer; Resnick, Michael A.; Bloom, Kerry

doi:10.1016/j.cub.2004.11.051

Cited by 143 publications

(152 citation statements)

References 19 publications

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“…7C) such as the MRX complex or the Rad52 protein (Kaye et al 2004;Lobachev et al 2004). Inability to maintain end coordination when the donors are physically separated could then result in loss of signaling between the ends, causing a shift from the quick and efficient GC mode of repair to the slow and inefficient BIR mode of repair (Fig.…”

Section: Discussionmentioning

confidence: 99%

A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair

Jain¹,

Sugawara²,

Lydeard³

et al. 2009

Genes Dev.

129

224

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A DNA double-strand break (DSB) is repaired by gene conversion (GC) if both ends of the DSB share homology with an intact DNA sequence. However, if homology is limited to only one of the DSB ends, repair occurs by break-induced replication (BIR). It is not known how the homology status of the DSB ends is first assessed and what other parameters govern the choice between these repair pathways. Our data suggest that a ''recombination execution checkpoint'' (REC) regulates the choice of the homologous recombination pathway employed to repair a given DSB. This choice is made prior to the initiation of DNA synthesis, and is dependent on the relative position and orientation of the homologous sequences used for repair. The RecQ family helicase Sgs1 plays a key role in regulating the choice of the recombination pathway. Surprisingly, break repair and gap repair are fundamentally different processes, both kinetically and genetically, as Pol32 is required only for gap repair. We propose that the REC may have evolved to preserve genome integrity by promoting conservative repair, especially when a DSB occurs within a repeated sequence. Eukaryotic cells have evolved several mechanisms to repair DNA lesions and maintain genome integrity. DNA double-strand breaks (DSBs) can be repaired either by nonhomologous end joining (NHEJ), involving simple religation of the broken DNA ends, or by homologous recombination (HR), in which genetic information from an intact homologous locus is used as a template for repair (Pâ ques and Haber 1999;Krogh and Symington 2004). Repair by HR involves extensive 59-to-39 resection of the broken DNA ends, which leaves 39-ended single-stranded tails of DNA that subsequently get coated with the Rad51 recombinase protein. This Rad51-DNA filament searches for and base-pairs with (synapses with) a homologous donor, forming a three-strand structure called the displacement loop or D-loop. The 39 end of the invaded strand primes new DNA synthesis to copy the donor template, leading to repair of the break. When both ends of a DSB share homology with a sister chromatid, a homologous chromosome or an ectopically located donor, the break is usually repaired by gene conversion (GC), in which a relatively short patch of new DNA is synthesized. If the homologies to the two DSB ends are separated by an insertion, the GC event is called gap repair as opposed to simple break repair, which occurs when there is no gap between the homologous donors. In mitotic cells, GC-associated DNA synthesis most often occurs in apparently sequential steps by synthesis-dependent strand annealing (Ira et al. 2006), although repair involving a more stable double-Holliday junction intermediate is also possible (Ira et al. 2003).When homology with only one of the DSB ends is present, repair occurs by break-induced replication (BIR) (Fig. 1B). The initial steps of Rad51 filament formation, homology searching, and strand invasion are thought to be similar, if not identical, in GC and BIR. However, in the absence of a second end that can ei...

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Section: Discussionmentioning

confidence: 99%

A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair

Jain¹,

Sugawara²,

Lydeard³

et al. 2009

Genes Dev.

129

224

View full text Add to dashboard Cite

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“…Mre11 has 39 to 59 exonuclease activity and both Mre11 and Sae2 have endonuclease activity (Bressan et al 1998;Lee et al 2002;Nicolette et al 2010); however, mutation of the nuclease activity of Mre11 has very little effect on resection (Bressan et al 1998;Moreau et al 1999;Lee et al 2002). Mre11's nuclease activity is required in mitotic cells to cleave hairpin ends (Lobachev et al 2004;Yu et al 2004) and in meiosis to remove the Spo11 protein from DSB ends (but in both of these cases Sae2 is also necessary). Deleting Sae2 does significantly retard resection (Clerici et al 2005).…”

Section: For Details)mentioning

confidence: 99%

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

2012

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Mating type in Saccharomyces cerevisiae is determined by two nonhomologous alleles, MATa and MATa. These sequences encode regulators of the two different haploid mating types and of the diploids formed by their conjugation. Analysis of the MATa1, MATa1, and MATa2 alleles provided one of the earliest models of cell-type specification by transcriptional activators and repressors. Remarkably, homothallic yeast cells can switch their mating type as often as every generation by a highly choreographed, site-specific homologous recombination event that replaces one MAT allele with different DNA sequences encoding the opposite MAT allele. This replacement process involves the participation of two intact but unexpressed copies of mating-type information at the heterochromatic loci, HMLa and HMRa, which are located at opposite ends of the same chromosome-encoding MAT. The study of MAT switching has yielded important insights into the control of cell lineage, the silencing of gene expression, the formation of heterochromatin, and the regulation of accessibility of the donor sequences. Real-time analysis of MAT switching has provided the most detailed description of the molecular events that occur during the homologous recombinational repair of a programmed double-strand chromosome break. TABLE OF CONTENTS Abstract 33Introduction 34

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“…The interaction between DatmA and bimE could reveal a relationship between DSBs and the mitotic spindle checkpoint. Lobachev et al (2004) have shown that the Mre11 complex is required in vivo to hold the two ends of a broken chromosome together throughout DSB repair. The same authors have shown that a mutation in the Rad50 Zn-hook structure resulted in DNA ends that are dispersed in 10-20% of cells.…”

Section: Chk2mentioning

confidence: 99%

“…The same authors have shown that a mutation in the Rad50 Zn-hook structure resulted in DNA ends that are dispersed in 10-20% of cells. The Mre11 complex holds broken ends together and counteracts mitotic spindle forces that can be destructive to damaged chromosomes (Lobachev et al 2004). Malavazi et al (2005) have shown epistatic and synergistic interactions between sldI RAD50 and bimE APC1 at S-phase checkpoints and in response to HU and UV light.…”

Section: Chk2mentioning

confidence: 99%

Genetic Interactions of the Aspergillus nidulans atmAATM Homolog With Different Components of the DNA Damage Response Pathway

Malavazi¹,

Lima²,

Castro³

et al. 2008

Genetics

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Ataxia telangiectasia mutated (ATM) is a phosphatidyl-3-kinase-related protein kinase that functions as a central regulator of the DNA damage response in eukaryotic cells. In humans, mutations in ATM cause the devastating neurodegenerative disease ataxia telangiectasia. Previously, we characterized the homolog of ATM (AtmA) in the filamentous fungus Aspergillus nidulans. In addition to its expected role in the DNA damage response, we found that AtmA is also required for polarized hyphal growth. Here, we extended these studies by investigating which components of the DNA damage response pathway are interacting with AtmA. The AtmA ATM loss of function caused synthetic lethality when combined with mutation in UvsB ATR . Our results suggest that AtmA and UvsB are interacting and they are probably partially redundant in terms of DNA damage sensing and/or repairing and polar growth. We identified and inactivated A. nidulans chkA CHK1 and chkB CHK2 genes. These genes are also redundantly involved in A. nidulans DNA damage response. We constructed several combinations of double mutants for DatmA, DuvsB, DchkA, and DchkB. We observed a complex genetic relationship with these mutations during the DNA replication checkpoint and DNA damage response. Finally, we observed epistatic and synergistic interactions between AtmA, and bimE APC1, ankA WEE1 and the cdc2-related kinase npkA, at S-phase checkpoint and in response to DNA-damaging agents.

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Chromosome Fragmentation after Induction of a Double-Strand Break Is an Active Process Prevented by the RMX Repair Complex

Cited by 143 publications

References 19 publications

A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair

A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

Genetic Interactions of the Aspergillus nidulans atmAATM Homolog With Different Components of the DNA Damage Response Pathway

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