Abstract
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.
Highlights
DNA double-strand breaks (DSBs) are the most deleterious DNA damage in cells
Consistent with the idea that TOP2-linked DSBs are predominantly repaired through nonhomologous end joining (NHEJ), TDP2 KO cells are more sensitive to etoposide than NBS1 depletion (Fig. 1b, d, g)
We have shown that conditional inactivation of NBS1 in germ cells leads to meiotic arrest and male infertility
Summary
DNA double-strand breaks (DSBs) are the most deleterious DNA damage in cells. DSBs can be repaired by either nonhomologous end joining (NHEJ) or homologous recombination (HR) [1, 2]. Since EXO1 or DNA2 cannot directly process DSBs that are covalently linked to proteins or chemicals, MRN complex-dependent endocleavage is required for resection of this type of DSBs. In somatic cells, Topoisomerase II (TOP2) resolves DNA catenanes during DNA replication and transcription by transiently cutting and ligating DNA [9]. TDP2 loss in mice does not affect meiotic progression or fertility, suggesting that NHEJ is not used for repairing meiotic SPO11linked DSBs [14]. To examine the function of MRN complex in meiotic DSB repair in mice, we conditionally inactivate NBS1 in germ cells. NBS1 loss compromises the repair of SPO11-linked DSBs, disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.