ATM controls meiotic double-strand-break formation Journal Article

Authors: Lange, J.; Pan, J.; Cole, F.; Thelen, M. P.; Jasin, M.; Keeney, S.
Article Title: ATM controls meiotic double-strand-break formation
Abstract: In many organisms, developmentally programmed double-strand breaks (DSBs) formed by the SPO11 transesterase initiate meiotic recombination, which promotes pairing and segregation of homologous chromosomes. Because every chromosome must receive a minimum number of DSBs, attention has focused on factors that support DSB formation. However, improperly repaired DSBs can cause meiotic arrest or mutation; thus, having too many DSBs is probably as deleterious as having too few. Only a small fraction of SPO11 protein ever makes a DSB in yeast or mouse and SPO11 and its accessory factors remain abundant long after most DSB formation ceases, implying the existence of mechanisms that restrain SPO11 activity to limit DSB numbers. Here we report that the number of meiotic DSBs in mouse is controlled by ATM, a kinase activated by DNA damage to trigger checkpoint signalling and promote DSB repair. Levels of SPO11-oligonucleotide complexes, by-products of meiotic DSB formation, are elevated at least tenfold in spermatocytes lacking ATM. Moreover, Atm mutation renders SPO11-oligonucleotide levels sensitive to genetic manipulations that modulate SPO11 protein levels. We propose that ATM restrains SPO11 via a negative feedback loop in which kinase activation by DSBs suppresses further DSB formation. Our findings explain previously puzzling phenotypes of Atm-null mice and provide a molecular basis for the gonadal dysgenesis observed in ataxia telangiectasia, the human syndrome caused by ATM deficiency. © 2011 Macmillan Publishers Limited. All rights reserved.
Keywords: controlled study; dna-binding proteins; nonhuman; chromosome; mouse; phenotype; spermatocyte; meiosis; animals; cell cycle proteins; mice; spermatocytes; mus; animal experiment; protein; enzyme activity; genetic manipulation; protein-serine-threonine kinases; tumor suppressor proteins; molecular analysis; atm protein; dna breaks, double-stranded; double stranded dna break; rodent; negative feedback; gene dosage; oligonucleotide; feedback, physiological; testis; chromosome segregation; spo11 protein; ataxia telangiectasia; endodeoxyribonucleases; recombination; gonadal dysgenesis
Journal Title: Nature
Volume: 479
Issue: 7372
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2011-11-10
Start Page: 237
End Page: 240
Language: English
DOI: 10.1038/nature10508
PROVIDER: scopus
PMCID: PMC3213282
PUBMED: 22002603
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 9 December 2011" - "CODEN: NATUA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Scott N Keeney
    113 Keeney
  2. Julian Lange
    16 Lange
  3. Jing Pan
    7 Pan
  4. Maria Jasin
    224 Jasin
  5. Francesca Cole
    10 Cole