Inner Nuclear Envelope Proteins SUN1 and SUN2 Play a Prominent Role in the DNA Damage Response
Inner Nuclear Envelope Proteins SUN1 and SUN2 Play a Prominent Role in the DNA Damage Response
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DOI：
10.1016/j.cub.2012.06.043
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发表时间：
2012-09-11
期刊：
影响因子：
9.2
通讯作者：
Han, Min
中科院分区：
文献类型：
--
作者：
Lei, Kai;Zhu, Xiaoqiang;Han, Min
DNA 损伤反应 (DDR) 和 DNA 修复对于维持基因组稳定性和避免许多人类疾病至关重要 [1, 2]。最近的研究结果表明，核膜 (NE) 蛋白 SUN1 的积累是 Emery-Dreifuss 肌营养不良症和 Hutchinson-Gilford 早衰综合征的重要致病事件，这两种疾病都是由 LMNA 突变引起的 [3, 4]。然而，哺乳动物 SUN 蛋白在有丝分裂细胞分裂和基因组稳定性中的作用尚不清楚。在这里，我们报道内部NE蛋白SUN1和SUN2可能在DDR中发挥冗余作用。 Sun1(-/-) Sun2(-/-) 小鼠的小鼠胚胎成纤维细胞在细胞周期的 S 期表现出过早增殖停滞、细胞凋亡和 DNA 损伤增加以及核周异染色质减少，表明基因组不稳定。此外，ATM 和 H2A.X 的激活（DDR 中的早期事件）在 Sun1(-/-) Sun2(-/-) 成纤维细胞中受损。生化筛选确定了 SUN1 和 SUN2 与 DNA 依赖性蛋白激酶 (DNAPK) 复合物之间的相互作用，该复合物在 DNA 非同源末端连接修复中发挥作用，并可能在 DDR 中发挥作用 [2,5,6]。 DNAPK 的敲除减少了 NIH 3T3 细胞中 ATM 的激活，这与 DDR 期间 SUN1-和 SUN2-DNAPK 相互作用的潜在作用一致。 SUN1 和 SUN2 可能通过将某些核因子定位到 NE 或通过介导核事件和细胞质事件之间的通讯来影响 DDR。
The DNA damage response (DDR) and DNA repair are critical for maintaining genomic stability and evading many human diseases [1, 2]. Recent findings indicate that accumulation of SUN1, a nuclear envelope (NE) protein, is a significant pathogenic event in Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome, both caused by mutations in LMNA [3, 4]. However, roles of mammalian SUN proteins in mitotic cell division and genomic stability are unknown. Here we report that the inner NE proteins SUN1 and SUN2 may play a redundant role in DDR. Mouse embryonic fibroblasts from Sun1(-/-) Sun2(-/-) mice displayed premature proliferation arrest in S phase of cell cycle, increased apoptosis and DNA damage, and decreased perinuclear heterochromatin, indicating genome instability. Furthermore, activation of ATM and H2A.X, early events in DDR, were impaired in Sun1(-/-) Sun2(-/-) fibroblasts. A biochemical screen identified interactions between SUN1 and SUN2 and DNA-dependent protein kinase (DNAPK) complex that functions in DNA nonhomologous end joining repair and possibly in DDR [2, 5, 6]. Knockdown of DNAPK reduced ATM activation in NIH 3T3 cells, consistent with a potential role of SUN1- and SUN2-DNAPK interaction during DDR. SUN1 and SUN2 could affect DDR by localizing certain nuclear factors to the NE or by mediating communication between nuclear and cytoplasmic events.