ATM controls meiotic double-strand-break formation

Nature. 2011 Oct 16;479(7372):237-40. doi: 10.1038/nature10508.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Chromosome Segregation
  • DNA Breaks, Double-Stranded*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endodeoxyribonucleases / biosynthesis
  • Endodeoxyribonucleases / genetics
  • Endodeoxyribonucleases / metabolism
  • Feedback, Physiological
  • Gene Dosage
  • Male
  • Meiosis*
  • Mice
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Spermatocytes / metabolism
  • Testis / cytology
  • Testis / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Endodeoxyribonucleases
  • meiotic recombination protein SPO11