Broering Tyler J, Wang Yuan-Liang, Pandey Ram Naresh, Hegde Rashmi S, Wang Shao-Chun, Namekawa Satoshi H
Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Biol Open. 2015 May 15;4(7):873-84. doi: 10.1242/bio.011734.
Meiosis is precisely regulated by the factors involved in DNA damage response in somatic cells. Among them, phosphorylation of H2AX on Serine 139 (γH2AX) is an essential signal for the silencing of unsynapsed sex chromosomes during male meiosis. However, it remains unknown how adjacent H2AX phosphorylation on Tyrosine 142 (pTyr142) is regulated in meiosis. Here we investigate the meiotic functions of BAZ1B (WSTF), the only known Tyr142 kinase in somatic cells, using mice possessing a conditional deletion of BAZ1B. Although BAZ1B deletion causes ectopic γH2AX signals on synapsed autosomes during the early pachytene stage, BAZ1B is dispensable for fertility and critical events during spermatogenesis. BAZ1B deletion does not alter events on unsynapsed axes and pericentric heterochromatin formation. Furthermore, BAZ1B is dispensable for localization of the ATP-dependent chromatin remodeling protein SMARCA5 (SNF2h) during spermatogenesis despite the complex formation between BAZ1B and SMARCA5, known as the WICH complex, in somatic cells. Notably, pTyr142 is regulated independently of BAZ1B and is dephosphorylated on the sex chromosomes during meiosis in contrast with the presence of adjacent γH2AX. Dephosphorylation of pTyr142 is regulated by MDC1, a binding partner of γH2AX. These results reveal the distinct regulation of two adjacent phosphorylation sites of H2AX during meiosis, and suggest that another kinase mediates Tyr142 phosphorylation.
减数分裂由体细胞中参与DNA损伤反应的因子精确调控。其中，丝氨酸139位点的H2AX磷酸化（γH2AX）是雄性减数分裂过程中未联会性染色体沉默的重要信号。然而，酪氨酸142位点的相邻H2AX磷酸化（pTyr142）在减数分裂中是如何调控的仍不清楚。在这里，我们使用条件性缺失BAZ1B的小鼠研究了体细胞中唯一已知的Tyr142激酶BAZ1B（WSTF）的减数分裂功能。尽管BAZ1B缺失在粗线期早期导致联会常染色体上出现异位γH2AX信号，但BAZ1B对于生育能力和精子发生过程中的关键事件是可有可无的。BAZ1B缺失不会改变未联会轴上的事件和着丝粒周围异染色质的形成。此外，尽管在体细胞中BAZ1B和ATP依赖的染色质重塑蛋白SMARCA5（SNF2h）之间形成了称为WICH复合体的复合物，但BAZ1B对于精子发生过程中SMARCA5的定位是可有可无的。值得注意的是，pTyr142的调控独立于BAZ1B，并且在减数分裂过程中，与相邻γH2AX的存在相反，性染色体上的pTyr142会去磷酸化。pTyr142的去磷酸化由γH2AX的结合伴侣MDC1调控。这些结果揭示了减数分裂过程中H2AX两个相邻磷酸化位点的不同调控，并表明另一种激酶介导了Tyr142的磷酸化。
