ATM controls meiotic double-strand-break formation

Lange, Julian; Pan, Jing; Cole, Francesca; Thelen, Michael P.; Jasin, Maria; Keeney, Scott

doi:10.1038/nature10508

Cited by 240 publications

(361 citation statements)

References 28 publications

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“…Consistent with our results in mouse somatic cells, however, recent studies have shown that ATM is not required for meiotic recombination, like when Spo11 gene dosage is reduced (50), but rather, that ATM plays an important role in regulating DSB levels during meiosis (51). In mitotically dividing cells, ATM has been reported to suppress spontaneous homologous recombination (52,53); increased recombination in the absence of ATM may result from increased numbers of lesions from defective DNA damage signaling or repair.…”

Section: Discussionsupporting

confidence: 89%

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Kass¹,

Helgadottir

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1, a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.

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Section: Discussionsupporting

confidence: 89%

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Kass¹,

Helgadottir

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The uterine lining does not show evidence of proliferation or degeneration, and there is no estrous cycling (24). This may be attributed to Atm control of the number of meiotic double-strand-break (DSB) created by Spo11, important for meiotic recombination during gametogenesis in spermatogonia and priomordial follicle (23,24,30). This mechanism may partially explain the finding of sexual dimorphism: in males, disruption of meiosis would be expected to affect mainly spermatogenesis, while testosterone production by Leydig cells would not be affected.…”

Section: Discussionmentioning

confidence: 99%

Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort

et al. 2016

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Background: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. Methods: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. results: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (−1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. conclusion: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.

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“…We therefore postulate that ATR negatively regulates DMC1 abundance by limiting its deposition to only one end of a processed meiotic DSB site and by preventing the formation of supernumerary meiotic DSBs. Two recent publications demonstrate that ATM also acts as a negative regulator of meiotic DSB formation in mouse and fly (Joyce et al, 2011;Lange et al, 2011). Further efforts are needed to clarify to what extent ATM and ATR negatively control meiotic DSB formation in Arabidopsis.…”

Section: Discussionmentioning

confidence: 99%

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

et al. 2012

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Meiosis ensures the reduction of the genome before the formation of generative cells and promotes the exchange of genetic information between homologous chromosomes by recombination. Essential for these events are programmed DNA double strand breaks (DSBs) providing single-stranded DNA overhangs after their processing. These overhangs, together with the RADiation sensitive51 (RAD51) and DMC1 Disrupted Meiotic cDNA1 (DMC1) recombinases, mediate the search for homologous sequences. Current models propose that the two ends flanking a meiotic DSB have different fates during DNA repair, but the molecular details remained elusive. Here we present evidence, obtained in the model plant Arabidopsis thaliana, that the two recombinases, RAD51 and DMC1, localize to opposite sides of a meiotic DSB. We further demonstrate that the ATR kinase is involved in regulating DMC1 deposition at meiotic DSB sites, and that its elimination allows DMC1-mediated meiotic DSB repair even in the absence of RAD51. DMC1's ability to promote interhomolog DSB repair is not a property of the protein itself but the consequence of an ASYNAPTIC1 (Hop1)-mediated impediment for intersister repair. Taken together, these results demonstrate that DMC1 functions independently and spatially separated from RAD51 during meiosis and that ATR is an integral part of the regular meiotic program.

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ATM controls meiotic double-strand-break formation

Cited by 240 publications

References 28 publications

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

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