title: MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells.
abstract: Chromosome-wide inactivation is an epigenetic signature of sex chromosomes. The mechanism by which the chromosome-wide domain is recognized and gene silencing is induced remains unclear. Here we identify an essential mechanism underlying the recognition of the chromosome-wide domain in the male germline. We show that mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (γH2AX), defines the chromosome-wide domain, initiates meiotic sex chromosome inactivation (MSCI), and leads to XY body formation. Importantly, MSCI consists of two genetically separable steps. The first step is the MDC1-independent recognition of the unsynapsed axis by DNA damage response (DDR) factors such as ataxia telangiectasia and Rad3-related (ATR), TOPBP1, and γH2AX. The second step is the MDC1-dependent chromosome-wide spreading of DDR factors to the entire chromatin. Furthermore, we demonstrate that, in somatic cells, MDC1-dependent amplification of the γH2AX signal occurs following replicative stress and is associated with transcriptional silencing. We propose that a common DDR pathway underlies both MSCI and the response of somatic cells to replicative stress. These results establish that the DDR pathway centered on MDC1 triggers epigenetic silencing of sex chromosomes in germ cells.
authors.affiliation: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ichijima
authors.forename: Misako
authors.initials: M
authors.lastname: Ichijima
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Camerini-Otero
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Satoshi H
authors.initials: SH
authors.lastname: Namekawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D004303:Dosage Compensation, Genetic / Q000235:genetics*; D005260:Female; D006570:Heterochromatin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011995:Recombination, Genetic; D012730:Sex Chromosomes / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism*; D013737:Testis / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006570:Heterochromatin; D047908:Intracellular Signaling Peptides and Proteins; C508937:MDC1 protein, mouse; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases