MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells

Yosuke Ichijima, Misako Ichijima, Zhenkun Lou, André Nussenzweig, R. Daniel Camerini-Otero, Junjie Chen, Paul R. Andreassen, Satoshi H. Namekawa

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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 gH2AX 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.

Original languageEnglish (US)
Pages (from-to)959-971
Number of pages13
JournalGenes and Development
Volume25
Issue number9
DOIs
StatePublished - May 1 2011

Keywords

  • DNA damage response
  • Germ cells
  • MDC1
  • Meiosis
  • Meiotic sex chromosome inactivation
  • γH2AX

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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