Regulation of the DNA damage response on male meiotic sex chromosomes

Abstract

During meiotic prophase in males, the sex chromosomes partially synapse to form the XY body. This is a unique structure that recruits proteins involved in the DNA damage response, which is believed to be important for silencing of the sex chromosomes. It remains elusive how the DNA damage response in the XY body is regulated. H2AX-MDC1-RNF8 signaling, which is well characterized in somatic cells, is dispensable for the recruitment of proteins to the unsynapsed axes in the XY body. However, the DNA damage response that spreads over the sex chromosomes is largely similar to that in somatic cells. Here we show that accumulation of some components of the DNA damage response pathway on the XY body occurs upstream of H2AX-MDC1-RNF8 signalling, and downstream from this cascade of events for others. This analysis shows that there are important differences between the regulation of the DNA damage response at the XY body and at DNA damage sites in somatic cells.

Double-strand break repair on sex chromosomes: challenges during male meiotic prophase

“…For example, gH2AX-MDC1-RNF8 is a well characterized phosphorylation-dependent DNA damage signaling pathway in response to DSBs in somatic cells 46,47 and all 3 proteins spread over chromosome loops. 29 Consistently, RNF8-depedent histone ubiquitination as well as downstream partners such as RAD18 and 53BP1 are also found in chromosome loops. 29 Other proteins implicated in DNA damage signaling also cover the entire sex chromosome, such as MCPH1 48 and sumoylated protein.…”

“…29 Since pachytene lasts for several days during mouse postnatal development, 36 meiotic cells in this stage could be easily identified, which allows to study the prolonged DNA damage response in the XY body. Interestingly, DNA damage response proteins localize at 2 different regions inside the XY body.…”

“…However, DNA repair is not finished in sex chromosomes and gH2AX signals remain in sex chromosomes 28 along with many other DNA damage response proteins. 29 At late pachytene, male sex chromosomes are isolated in a subnuclear structure known as the XY body. DNA damage response proteins remain in the XY body till late diplotene, suggesting that DSB repair is significantly delayed in male sex chromosomes.…”

“…Interestingly, DNA damage response proteins localize at 2 different regions inside the XY body. 29 While some proteins cover the entire XY body, others exclusively localize at chromosome axes associated with axial elements of synaptonemal complex, such as SYCP3 (Fig. 2).…”

CHFR is important for the survival of male premeiotic germ cells

“…In addition, these proteins are assembled through a unique mechanism to repair the breaks on male sex chromosomes, which share little homology. 5 In agreement with these important functions, meiosis in knockout mice for H2AX, MDC1, and ATM arrests before the onset of meiotic division. [6][7][8][9] Another group of DNA damage response proteins functions in spermiogenesis, during which haploid round spermatids elongate and compact their nucleus.…”