Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, Guangdong, China.
Biol Reprod. 2022 Jul 25;107(1):168-182. doi: 10.1093/biolre/ioac054.
During male meiosis, the constitutively unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI), and the DNA damage response (DDR) pathway is critical for MSCI establishment. Our previous study showed that UHRF1 (ubiquitin-like, with PHD and ring finger domains 1) deletion led to meiotic arrest and male infertility; however, the underlying mechanisms of UHRF1 in the regulation of meiosis remain unclear. Here, we report that UHRF1 is required for MSCI and cooperates with the DDR pathway in male meiosis. UHRF1-deficient spermatocytes display aberrant pairing and synapsis of homologous chromosomes during the pachytene stage. In addition, UHRF1 deficiency leads to aberrant recruitment of ATR and FANCD2 on the sex chromosomes and disrupts the diffusion of ATR to the XY chromatin. Furthermore, we show that UHRF1 acts as a cofactor of BRCA1 to facilitate the recruitment of DDR factors onto sex chromosomes for MSCI establishment. Accordingly, deletion of UHRF1 leads to the failure of meiotic silencing on sex chromosomes, resulting in meiotic arrest. In addition to our previous findings, the present study reveals that UHRF1 participates in MSCI, ensuring the progression of male meiosis. This suggests a multifunctional role of UHRF1 in the male germline.
在雄性减数分裂过程中，常染色体上的 X 和 Y 染色体始终不进行联会，从而发生减数分裂性染色体失活（meiotic sex chromosome inactivation，MSCI），而 DNA 损伤反应（DNA damage response，DDR）途径对 MSCI 的建立至关重要。我们之前的研究表明，UHRF1（泛素样，含 PHD 和环指结构域 1）缺失会导致减数分裂停滞和雄性不育；然而，UHRF1 在调控减数分裂过程中的作用机制尚不清楚。在这里，我们报告 UHRF1 是 MSCI 所必需的，并且与雄性减数分裂中的 DDR 途径合作。UHRF1 缺陷型精母细胞在粗线期表现出同源染色体的异常配对和联会。此外，UHRF1 缺失导致 ATR 和 FANCD2 异常募集到性染色体上，并破坏了 ATR 向 XY 染色质的扩散。此外，我们表明 UHRF1 作为 BRCA1 的辅助因子，促进 DDR 因子募集到性染色体上以建立 MSCI。因此，UHRF1 的缺失导致性染色体上的减数沉默失败，从而导致减数分裂停滞。除了我们之前的发现，本研究揭示了 UHRF1 参与 MSCI，确保了雄性减数分裂的进行。这表明 UHRF1 在雄性生殖细胞中具有多功能作用。
