ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes.
During meiosis in most sexually reproducing organisms, recombination forms crossovers between homologous maternal and paternal chromosomes and thereby promotes proper chromosome segregation at the first meiotic division. The number and distribution of crossovers are tightly controlled, but the factors that contribute to this control are poorly understood in most organisms, including mammals. Here we provide evidence that the ATM kinase or protein is essential for proper crossover formation in mouse spermatocytes. ATM deficiency causes multiple phenotypes in humans and mice, including gonadal atrophy. Mouse Atm-/- spermatocytes undergo apoptosis at mid-prophase of meiosis I, but Atm(-/-) meiotic phenotypes are partially rescued by Spo11 heterozygosity, such that ATM-deficient spermatocytes progress to meiotic metaphase I. Strikingly, Spo11+/-Atm-/- spermatocytes are defective in forming the obligate crossover on the sex chromosomes, even though the XY pair is usually incorporated in a sex body and is transcriptionally inactivated as in normal spermatocytes. The XY crossover defect correlates with the appearance of lagging chromosomes at metaphase I, which may trigger the extensive metaphase apoptosis that is observed in these cells. In addition, control of the number and distribution of crossovers on autosomes appears to be defective in the absence of ATM because there is an increase in the total number of MLH1 foci, which mark the sites of eventual crossover formation, and because interference between MLH1 foci is perturbed. The axes of autosomes exhibit structural defects that correlate with the positions of ongoing recombination. Together, these findings indicate that ATM plays a role in both crossover control and chromosome axis integrity and further suggests that ATM is important for coordinating these features of meiotic chromosome dynamics.
Barchi
Marco
M
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Roig
Ignasi
I
Di Giacomo
Monica
M
de Rooij
Dirk G
DG
Keeney
Scott
S
Jasin
Maria
M
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002869:Chromosome Aberrations; D023902:Chromosome Pairing; D003434:Crossing Over, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D004950:Esterases / Q000235:genetics; D005260:Female; D006579:Heterozygote; D008297:Male; D008540:Meiosis; D008677:Metaphase; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012730:Sex Chromosomes / Q000235:genetics*; D013090:Spermatocytes / Q000166:cytology / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099257:Meiotic Recombination Protein SPO11
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004950:Esterases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D000099257:Meiotic Recombination Protein SPO11; C576324:ATM protein, human; C576325:Atm protein, mouse