Document Detail

Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants.
MedLine Citation:
PMID:  15640358     Owner:  NLM     Status:  MEDLINE    
Defects in meiotic recombination in many organisms result in arrest because of activation of a meiotic checkpoint(s). The proximal defect that triggers this checkpoint in mammalian germ cells is not understood, but it has been suggested to involve either the presence of DNA damage in the form of unrepaired recombination intermediates or defects in homologous chromosome pairing and synapsis independent of DNA damage per se. To distinguish between these possibilities in the female germ line, we compared mouse oocyte development in a mutant that fails to form the double-strand breaks (DSBs) that initiate meiotic recombination (Spo11-/-) to mutants with defects in processing DSBs when they are formed (Dmc1-/- and Msh5-/-), and we examined the epistasis relationships between these mutations. Absence of DSB formation caused a partial defect in follicle formation, whereas defects in DSB repair caused earlier and more severe meiotic arrest, which could be suppressed by eliminating DSB formation. Therefore, our analysis reveals that there are both DNA-damage-dependent and -independent responses to recombination errors in mammalian oocytes. By using these findings as a paradigm, we also examined oocyte loss in mutants lacking the DNA-damage checkpoint kinase ATM. The absence of ATM caused defects in folliculogenesis that were similar to those in Dmc1 mutants and that could be suppressed by Spo11 mutation, implying that oocyte death in Atm-deficient animals is a response to defective DSB repair.
Monica Di Giacomo; Marco Barchi; Frédéric Baudat; Winfried Edelmann; Scott Keeney; Maria Jasin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-01-07
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  102     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2005-01-19     Completed Date:  2005-03-15     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  737-42     Citation Subset:  IM    
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center and Weill Graduate School of Medical Sciences of Cornell University, 1275 York Avenue, New York, NY 10021, USA.
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MeSH Terms
Cell Cycle Proteins / genetics,  physiology
DNA Damage / physiology*
DNA-Binding Proteins / deficiency,  genetics,  physiology
Epistasis, Genetic
Esterases / deficiency,  genetics,  physiology
Mice, Knockout
Nuclear Proteins
Ovarian Follicle
Proteins / genetics,  physiology
Recombination, Genetic*
Synaptonemal Complex
Grant Support
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Dmc1h protein, mouse; 0/Msh5 protein, mouse; 0/Nuclear Proteins; 0/Proteins; EC 3.1.-/Endodeoxyribonucleases; EC 3.1.-/Esterases; EC 3.1.-/meiotic recombination protein SPO11

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