title: Meiotic functions of RAD18.
abstract: RAD18 is an ubiquitin ligase that is involved in replication damage bypass and DNA double-strand break (DSB) repair processes in mitotic cells. Here, we investigated the testicular phenotype of Rad18-knockdown mice to determine the function of RAD18 in meiosis, and in particular, in the repair of meiotic DSBs induced by the meiosis-specific topoisomerase-like enzyme SPO11. We found that RAD18 is recruited to a specific subfraction of persistent meiotic DSBs. In addition, RAD18 is recruited to the chromatin of the XY chromosome pair, which forms the transcriptionally silent XY body. At the XY body, RAD18 mediates the chromatin association of its interaction partners, the ubiquitin-conjugating enzymes HR6A and HR6B. Moreover, RAD18 was found to regulate the level of dimethylation of histone H3 at Lys4 and maintain meiotic sex chromosome inactivation, in a manner similar to that previously observed for HR6B. Finally, we show that RAD18 and HR6B have a role in the efficient repair of a small subset of meiotic DSBs.
authors.affiliation: Department of Reproduction and Development, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.forename: Esther
authors.initials: E
authors.lastname: Sleddens-Linkels
authors.forename: Evelyne
authors.initials: E
authors.lastname: Wassenaar
authors.forename: Marja
authors.initials: M
authors.lastname: Ooms
authors.forename: Wiggert A
authors.initials: WA
authors.lastname: van Cappellen
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Jost
authors.initials: J
authors.lastname: Seibler
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.forename: Myung K
authors.initials: MK
authors.lastname: Shin
authors.forename: J Anton
authors.initials: JA
authors.lastname: Grootegoed
authors.forename: Willy M
authors.initials: WM
authors.lastname: Baarends
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D013737:Testis / Q000378:metabolism* / Q000473:pathology; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D034741:RNA, Small Interfering; C485953:Rad18 protein, mouse; C512786:Ube2a protein, mouse; C465394:Ube2b protein, mouse; D044763:Ubiquitin-Conjugating Enzymes