# DNA Damage Response Pathways in Meiotic Sex Chromosome Inactivation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $184,800

## Abstract

ABSTRACT
The objective of this project is to elucidate the regulatory mechanisms and biological significance of the
epigenetic programming of the sex chromosomes in the male germline. During male meiosis, unsynapsed sex
chromosomes are epigenetically silenced in a process called meiotic sex chromosome inactivation (MSCI),
which is necessary for spermatogenesis. During the term of the previous grant, we elucidated the underlying
mechanisms of MSCI and demonstrated the role of DNA damage response (DDR) factors as essential
regulators. Establishment of MSCI requires phosphorylation of the histone variant H2AX (γH2AX) to spread
from the axes to the chromosome-wide domain of the sex chromosomes. This process is directed by MDC1, a
binding partner of γH2AX, at the onset of the pachytene stage. Downstream of MDC1, SCML2, a germline-
specific Polycomb protein, is recruited to γH2AX-containing nucleosomes and required for epigenetic
programming. During the last project period, we unexpectedly found that initiation of MSCI is tightly coupled to
active DNA demethylation. Initially the DNA demethylation is directed by MDC1 and precedes the
establishment of silent histone modifications. In this renewal application, we will test the central hypothesis that
the DDR pathway regulates active DNA demethylation, enabling the epigenetic programming of sex
chromosomes necessary for male reproduction. While DNA methylation is generally associated with gene
silencing, we propose that DNA demethylation is linked to gene silencing in MSCI. Our data suggest that
demethylation in MSCI involves two major phases: the initial phase is mediated by the DDR pathway at the
early pachytene stage (Aim 1) and the later phase is mediated by SCML2 downstream of the DDR at the mid-
pachytene stage (Aim 2). This study will establish a novel link between DDR signaling and active DNA
demethylation, and will further elucidate the biological significance of the epigenetic programming of the sex
chromosomes, which is essential for male reproduction.

## Key facts

- **NIH application ID:** 9867730
- **Project number:** 5R01GM098605-09
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Satoshi Namekawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,800
- **Award type:** 5
- **Project period:** 2011-08-01 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867730

## Citation

> US National Institutes of Health, RePORTER application 9867730, DNA Damage Response Pathways in Meiotic Sex Chromosome Inactivation (5R01GM098605-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9867730. Licensed CC0.

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