Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Cell Mol Life Sci. 2024 Mar 8;81(1):123. doi: 10.1007/s00018-024-05154-x.
Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.
维持基因组稳定性是增殖 NPC 确保遗传保真度的前提。尽管组蛋白精氨酸甲基化已被证明在保护基因组稳定性方面发挥着重要作用，但在大脑发育过程中的潜在机制尚不完全清楚。蛋白精氨酸 N-甲基转移酶 5（PRMT5）是一种 II 型蛋白精氨酸甲基转移酶，在转录调控中发挥作用。在这里，我们鉴定出 PRMT5 是 NPC 增殖过程中响应双链断裂（DSB）的 DNA 修复的关键调节剂。Prmt5;Emx1-Cre（cKO-Emx1）小鼠表现出独特的小头畸形表型，背侧内侧大脑皮层部分缺失，胼胝体和海马体完全缺失。这种表型是由于内侧背侧皮质中 DSBs 的积累，随后是细胞凋亡所致。RNA 测序和体外 DNA 修复分析均表明 PRMT5 是 DNA 同源重组（HR）修复所必需的。PRMT5 特异性地催化发育中小鼠脑中增殖 NPC 中的 H3R2me2s，以增强 DNA 修复过程中 HR 相关基因的表达。最后，BRCA1 的过表达可显著挽救 PRMT5 缺陷 NSCs 中 DSBs 的积累和细胞凋亡。总之，我们的研究结果表明 PRMT5 通过调节增殖 NPC 中的组蛋白精氨酸甲基化来维持基因组稳定性。
