MDC1 Directs Chromosome-wide Silencing of the Sex Chromosomes in Male Germ Cells

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2011 May 4

PMID 21536735

Citations 111

Authors

Yosuke Ichijima

Misako Ichijima

Zhenkun Lou

Andre Nussenzweig

R Daniel Camerini-Otero

Junjie Chen

Paul R Andreassen

Satoshi H Namekawa

Affiliations

Soon will be listed here.

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.

Citing Articles

CTCF-mediated 3D chromatin sets up the gene expression program in the male germline.

Kitamura Y, Takahashi K, Maezawa S, Munakata Y, Sakashita A, Katz S Nat Struct Mol Biol. 2025; .

PMID: 40033153 DOI: 10.1038/s41594-025-01482-z.

Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast.

Sottnik J, Shackleford M, Nesiba C, Richer A, Swartz J, Rowland C bioRxiv. 2024; .

PMID: 39677775 PMC: 11642799. DOI: 10.1101/2023.10.29.564555.

LARP7 is required for sex chromosome silencing during meiosis in mice.

Tando Y, Nonomura A, Ito-Matsuoka Y, Takehara A, Okamura D, Hayashi Y PLoS One. 2024; 19(12):e0314329.

PMID: 39637191 PMC: 11620648. DOI: 10.1371/journal.pone.0314329.

METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis.

Yin L, Jiang N, Xiong W, Yang S, Zhang J, Xiong M Adv Sci (Weinh). 2024; 12(3):e2406332.

PMID: 39607422 PMC: 11744674. DOI: 10.1002/advs.202406332.

ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse.

Menon D, Chakraborty P, Murcia N, Magnuson T Elife. 2024; 12.

PMID: 39589400 PMC: 11594533. DOI: 10.7554/eLife.88024.

References

Song R, Ro S, Michaels J, Park C, McCarrey J, Yan W . Many X-linked microRNAs escape meiotic sex chromosome inactivation. Nat Genet. 2009; 41(4):488-93. PMC: 2723799. DOI: 10.1038/ng.338. View

Wang J, Gong Z, Chen J . MDC1 collaborates with TopBP1 in DNA replication checkpoint control. J Cell Biol. 2011; 193(2):267-73. PMC: 3080258. DOI: 10.1083/jcb.201010026. View

Peters A, Plug A, van Vugt M, de Boer P . A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome Res. 1997; 5(1):66-8. DOI: 10.1023/a:1018445520117. View

Namekawa S, Lee J . XY and ZW: is meiotic sex chromosome inactivation the rule in evolution?. PLoS Genet. 2009; 5(5):e1000493. PMC: 2679206. DOI: 10.1371/journal.pgen.1000493. View

Celeste A, Petersen S, Romanienko P, Fernandez-Capetillo O, Chen H, Sedelnikova O . Genomic instability in mice lacking histone H2AX. Science. 2002; 296(5569):922-7. PMC: 4721576. DOI: 10.1126/science.1069398. View

McKee B, Handel M . Sex chromosomes, recombination, and chromatin conformation. Chromosoma. 1993; 102(2):71-80. DOI: 10.1007/BF00356023. View

Lu L, Wu J, Ye L, Gavrilina G, Saunders T, Yu X . RNF8-dependent histone modifications regulate nucleosome removal during spermatogenesis. Dev Cell. 2010; 18(3):371-84. PMC: 2840054. DOI: 10.1016/j.devcel.2010.01.010. View

Hall L, Byron M, Sakai K, Carrel L, Willard H, Lawrence J . An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells. Proc Natl Acad Sci U S A. 2002; 99(13):8677-82. PMC: 124357. DOI: 10.1073/pnas.132468999. View

Goldberg M, Stucki M, Falck J, DAmours D, Rahman D, Pappin D . MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature. 2003; 421(6926):952-6. DOI: 10.1038/nature01445. View

10.

Baudat F, Manova K, Yuen J, Jasin M, Keeney S . Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell. 2000; 6(5):989-98. DOI: 10.1016/s1097-2765(00)00098-8. View

11.

Plug A, Peters A, Keegan K, Hoekstra M, de Boer P, Ashley T . Changes in protein composition of meiotic nodules during mammalian meiosis. J Cell Sci. 1998; 111 ( Pt 4):413-23. DOI: 10.1242/jcs.111.4.413. View

12.

Shanbhag N, Rafalska-Metcalf I, Balane-Bolivar C, Janicki S, Greenberg R . ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell. 2010; 141(6):970-81. PMC: 2920610. DOI: 10.1016/j.cell.2010.04.038. View

13.

Cimprich K, Cortez D . ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8):616-27. PMC: 2663384. DOI: 10.1038/nrm2450. View

14.

Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J . Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997; 88(2):265-75. DOI: 10.1016/s0092-8674(00)81847-4. View

15.

Turner J, Mahadevaiah S, Ellis P, Mitchell M, Burgoyne P . Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids. Dev Cell. 2006; 10(4):521-9. DOI: 10.1016/j.devcel.2006.02.009. View

16.

van der Heijden G, Derijck A, Posfai E, Giele M, Pelczar P, Ramos L . Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation. Nat Genet. 2007; 39(2):251-8. DOI: 10.1038/ng1949. View

17.

Ahmed E, van der Vaart A, Barten A, Kal H, Chen J, Lou Z . Differences in DNA double strand breaks repair in male germ cell types: lessons learned from a differential expression of Mdc1 and 53BP1. DNA Repair (Amst). 2007; 6(9):1243-54. DOI: 10.1016/j.dnarep.2007.02.011. View

18.

Friedel A, Pike B, Gasser S . ATR/Mec1: coordinating fork stability and repair. Curr Opin Cell Biol. 2009; 21(2):237-44. DOI: 10.1016/j.ceb.2009.01.017. View

19.

Tarsounas M, Morita T, Pearlman R, Moens P . RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. J Cell Biol. 1999; 147(2):207-20. PMC: 2174216. DOI: 10.1083/jcb.147.2.207. View

20.

Chaumeil J, Le Baccon P, Wutz A, Heard E . A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev. 2006; 20(16):2223-37. PMC: 1553206. DOI: 10.1101/gad.380906. View