title: SPO11-independent DNA repair foci and their role in meiotic silencing.
abstract: In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11(YF/YF)), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11(YF/YF) and Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number of repair foci increased during oocyte development, indicating the induction of S phase-independent, de novo DNA damage. In wild type pachytene oocytes we observed meiotic silencing in two types of pseudo XY bodies, one type containing DMC1 and RAD51 foci on unsynapsed axes, and another type containing only RAD51 foci, mainly on synapsed axes. Taken together, our results indicate that in addition to asynapsis, persistent SPO11-induced DSBs are important for the initiation of MSCI and MSUC, and that SPO11-independent DNA repair foci contribute to the MSUC response in oocytes.
authors.affiliation: Department of Reproduction and Development, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Carofiglio
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.forename: Sandra
authors.initials: S
authors.lastname: de Vries
authors.forename: Evelyne
authors.initials: E
authors.lastname: Wassenaar
authors.forename: Sam
authors.initials: S
authors.lastname: Schoenmakers
authors.forename: Christie
authors.initials: C
authors.lastname: Vermeulen
authors.forename: Wiggert A
authors.initials: WA
authors.lastname: van Cappellen
authors.forename: Esther
authors.initials: E
authors.lastname: Sleddens-Linkels
authors.forename: J Anton
authors.initials: JA
authors.lastname: Grootegoed
authors.forename: Hein P J
authors.initials: HP
authors.lastname: Te Riele
authors.forename: Bernard
authors.initials: B
authors.lastname: de Massy
authors.forename: Willy M
authors.initials: WM
authors.lastname: Baarends
mesh_terms: D000818:Animals; D023902:Chromosome Pairing / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D009866:Oogenesis / Q000235:genetics; D013090:Spermatocytes / Q000166:cytology / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics*; D014998:Y Chromosome / Q000235:genetics; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D004706:Endodeoxyribonucleases; D000099257:Meiotic Recombination Protein SPO11