Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic function.

To deconvolute TOPBP1-dependent ATR signaling in male meiosis, we generated mice bearing multiple mutations in BRCT-domain 5 of TOPBP1. Topbp1B5/B5 males are sterile, having reduced testes size, reduced seminiferous tubule cellularity, and a complete loss of sperm. Strikingly, while Topbp1B5/B5 spermatocytes fail to progress properly, they display largely normal chromosome synapsis, sex body formation, and recruitment of DDR proteins to the X and Y during prophase I. Single-cell RNA sequencing data showed that while MSCI is initiated in Topbp1B5/B5, the dynamics of silencing progression and reinforcement is defective in prophase I. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation.

Congratulations Carol on your groundbreaking research and publication!