Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals.
Chromosome abnormalities are common in the human population, causing germ cell loss at meiotic prophase I and infertility. The mechanisms driving this loss are unknown, but persistent meiotic DNA damage and asynapsis may be triggers. Here we investigate the contribution of these lesions to oocyte elimination in mice with chromosome abnormalities, e.g. Turner syndrome (XO) and translocations. We show that asynapsed chromosomes trigger oocyte elimination at diplonema, which is linked to the presence of phosphorylated H2AFX (γH2AFX). We find that DNA double-strand break (DSB) foci disappear on asynapsed chromosomes during pachynema, excluding persistent DNA damage as a likely cause, and demonstrating the existence in mammalian oocytes of a repair pathway for asynapsis-associated DNA DSBs. Importantly, deletion or point mutation of H2afx restores oocyte numbers in XO females to wild type (XX) levels. Unexpectedly, we find that asynapsed supernumerary chromosomes do not elicit prophase I loss, despite being enriched for γH2AFX and other checkpoint proteins. These results suggest that oocyte loss cannot be explained simply by asynapsis checkpoint models, but is related to the gene content of asynapsed chromosomes. A similar mechanistic basis for oocyte loss may operate in humans with chromosome abnormalities.
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
Jeffrey M
JM
Cloutier
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
Shantha K
SK
Mahadevaiah
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
Elias
E
ElInati
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
André
A
Nussenzweig
Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
Attila
A
Tóth
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
James M A
JM
Turner
D000818:Animals; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000235:genetics; D023902:Chromosome Pairing / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D005260:Female; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D049469:Meiotic Prophase I / Q000235:genetics; D051379:Mice; D009865:Oocytes / Q000254:growth & development* / Q000378:metabolism; D010053:Ovary / Q000254:growth & development* / Q000378:metabolism; D011418:Prophase / Q000235:genetics; D014960:X Chromosome / Q000235:genetics
D006657:Histones; C475961:gamma-H2AX protein, mouse