NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis

DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic c...

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Bibliographic Details
Published in:Cell death and differentiation 2020-07, Vol.27 (7), p.2176-2190
Main Authors: Zhang, Bin, Tang, Zhenghui, Li, Lejun, Lu, Lin-Yu
Format: Article
Language:English
Subjects:
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Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Chromosomes
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Double-strand break repair
Germ cells
Homologous recombination
Infertility
Life Sciences
Meiosis
MRE11 protein
Prophase
Somatic cells
Stem Cells
Yeast
Zebrafish
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Summary:DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic cells, MRE11-RAD50-NBS1 (MRN) complex-dependent DNA end resection is a prerequisite for HR repair, especially for DSBs that are covalently linked with proteins or chemicals. Interestingly, all meiotic DSBs are linked with SPO11 after being generated. Although MRN complex’s function in meiotic DSB repair has been established in lower organisms, the role of MRN complex in mammalian meiotic DSB repair is not clear. Here, we show that MRN complex is essential for repairing meiotic SPO11-linked DSBs in male mice. In male germ cells, conditional inactivation of NBS1, a key component of MRN complex, causes dramatic reduction of DNA end resection and defective HR repair in meiotic prophase. NBS1 loss severely disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility in mice. Unlike in somatic cells, the recruitment of NBS1 to SPO11-linked DSB sites is MDC1-independent but requires other phosphorylated proteins. Collectively, our study not only reveals the significance of MRN complex in repairing meiotic DSBs but also discovers a unique mechanism that recruits MRN complex to SPO11-linked DSB sites.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-0493-4