Sex chromosome inactivation in germ cells: emerging roles of DNA damage response pathways

Abstract

Sex chromosome inactivation in male germ cells is a paradigm of epigenetic programming during sexual reproduction. Recent progress has revealed the underlying mechanisms of sex chromosome inactivation in male meiosis. The trigger of chromosome-wide silencing is activation of the DNA damage response (DDR) pathway, which is centered on the mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (γH2AX). This DDR pathway shares features with the somatic DDR pathway recognizing DNA replication stress in the S phase. Additionally, it is likely to be distinct from the DDR pathway that recognizes meiosis-specific double-strand breaks. This review article extensively discusses the underlying mechanism of sex chromosome inactivation.

Fig. 1

Schematic of sex chromosome inactivation in male germ cells. Meiotic chromosome axes appear in the leptotene stage, and start to synapse at the zygotene stage. In the pachytene stage, unsynapsed X and Y chromosomes are silenced (MSCI) and form a silent compartment XY body (or sex body). Silencing of the sex chromosomes persists into post-meiotic spermatids. The DDR pathway initiates MSCI. Subsequently, histone replacement occurs and epigenetic modifications are established specifically on the sex chromosomes. In the round spermatids, sex chromosomes occupy a silent compartment, PMSC, and nuclear histones are displaced by transition proteins (TNP1 and TNP2). The upper insets show representative pictures of the pachytene spermatocytes and round spermatids with DAPI staining, respectively. XY body and PMSC are circled

Fig. 2

The DDR-adapted model in meiotic silencing. There are two DDR pathways that underlie mammalian meiosis. a Spo11-dependent DSBs accompany the ATM-dependent DDR pathway and lead to meiotic recombination. After DNA end resection at DSBs, ATR is also activated on the ssDNA region. b Asynapsis regions are recognized by the ATR-dependent pathway, but are independent of ATM. This DDR pathway is distinct from the DSBs-associated DDR pathway and leads to meiotic silencing. MDC1 directs γH2AX amplification and chromosome-wide spreading. c In somatic DDR, the pathway following DSBs is regulated by ATM and is associated with silencing, DSBs repair, and checkpoint activation. d In somatic DDR, the ATR-dependent pathway is activated following DNA replication stress at the stalled replication fork in the S phase. At the stalled replication fork, ssDNA is recognized by RPA and the ATR-TOPBP1 complex is activated. This pathway is associated with silencing, DNA repair, and activation of the replication checkpoint

Fig. 3

A model of meiotic checkpoints in mammalian meiosis. DSBs is monitored by the ATM-dependent DDR pathway, and asynapsis is monitored by the ATR-dependent DDR pathway. In addition to these surveillance mechanisms, there is another layer of monitoring mechanisms in the meiotic progression. This putative pachytene checkpoint is associated with germ cell loss at the mid-pachytene stages that correspond to testicular stage IV