UHRF1 is indispensable for meiotic sex chromosome inactivation and interacts with the DNA damage response pathway in mice
UHRF1 is indispensable for meiotic sex chromosome inactivation and interacts with the DNA damage response pathway in mice
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DOI：
10.1093/biolre/ioac054
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发表时间：
2022-01
影响因子：
3.6
通讯作者：
Mengneng Xiong;Shumin Zhou;Shenglei Feng;Yiqian Gui;Jinmei Li;Yanqing Wu;Juan Dong;Shuiqiao Yuan-Sh
中科院分区：
文献类型：
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作者：
Mengneng Xiong;Shumin Zhou;Shenglei Feng;Yiqian Gui;Jinmei Li;Yanqing Wu;Juan Dong;Shuiqiao Yuan-Sh
摘要 在雄性减数分裂过程中，组成型非突触的 XY 染色体经历减数分裂性染色体失活（MSCI），而 DNA 损伤反应（DDR）途径对于 MSCI 的建立至关重要。我们之前的研究表明，UHRF1（泛素样，具有PHD和无名指结构域1）缺失会导致减数分裂停滞和男性不育；然而，UHRF1 调节减数分裂的潜在机制仍不清楚。在此，我们报道 UHRF1 是 MSCI 所必需的，并与雄性减数分裂中的 DDR 途径配合。 UHRF1 缺陷的精母细胞在粗线期表现出同源染色体的异常配对和突触。此外，UHRF1 缺陷导致 ATR 和 FANCD2 在性染色体上异常招募，并破坏 ATR 向 XY 染色质的扩散。此外，我们发现 UHRF1 作为 BRCA1 的辅助因子，促进 DDR 因子招募到性染色体上，以建立 MSCI。因此，UHRF1 的缺失会导致性染色体减数分裂沉默失败，从而导致减数分裂停滞。除了我们之前的发现之外，本研究还表明 UHRF1 参与 MSCI，确保雄性减数分裂的进展。这表明 UHRF1 在雄性种系中具有多功能作用。摘要句子 UHRF1 直接与 BRCA1 相互作用，并在减数分裂性染色体失活 (MSCI) 中发挥关键作用。图解摘要
Abstract 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. Summary Sentence UHRF1 is directly interacts with BRCA1 and has critical role in meiotic sex chromosome inactivation (MSCI). Graphical Abstract