Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair
Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair
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E2F转录因子的负调节因子将细胞周期检查点和DNA损伤修复联系起来
DOI：
10.1073/pnas.1720094115
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发表时间：
2018-04-17
影响因子：
11.1
通讯作者：
Yan, Shunping
中科院分区：
文献类型：
--
作者：
Wang, Lili;Chen, Hanchen;Yan, Shunping
DNA经常受到内源性和外源性因素的损伤。作为对DNA损伤的反应，细胞激活检查点来阻止细胞周期的进展，为DNA修复提供足够的时间。DNA修复缺陷导致包括癌症在内的许多疾病。E2F转录因子在细胞周期进程中起关键作用，并受肿瘤抑制蛋白视网膜母细胞瘤的负调控。在这项研究中，我们证明了DNA修复蛋白SNI1， SMC5/6复合体的一个亚基，是E2Fs的负调控因子。此外，本研究还表明，检查点和DNA修复与SNI1直接相关，为DNA损伤反应提供了见解。DNA损伤严重威胁基因组完整性，严重影响生长发育。为了维持基因组的稳定性，所有生物都进化出了复杂的DNA损伤反应机制，包括细胞周期检查点的激活和DNA修复。在这里，我们发现DNA修复蛋白SNI1是进化上保守的SMC5/6复合体的一个亚基，在拟南芥中直接连接了这两个过程。SNI1结合细胞周期进程的关键调控因子E2F转录因子的激活域，并抑制其转录活性。反过来，E2Fs激活SNI1的表达，这表明E2Fs和SNI1形成了一个负反馈回路。从遗传学上讲，过表达SNI1会抑制过表达E2F的植株的表型，而丧失E2F功能则会完全抑制SNI1突变体，这表明SNI1是抑制E2F的必要和充分条件。总之，我们的研究揭示了SNI1是E2Fs的负调控因子，并通过连接细胞周期检查点和DNA修复在DNA损伤应答中发挥双重作用。
Significance DNA is frequently damaged by both endogenous and exogenous factors. In response to DNA damage, cells activate checkpoints to arrest cell cycle progression, allowing sufficient time for DNA repair. Defects in DNA repair cause many diseases including cancers. The E2F transcription factors are key players in cell cycle progression and are negatively regulated by the tumor suppressor protein Retinoblastoma. In this study, we demonstrated that the DNA repair protein SNI1, a subunit of SMC5/6 complex, is a negative regulator of E2Fs. In addition, this study also suggests that checkpoint and DNA repair are directly linked by SNI1, providing insights into DNA damage responses. DNA damage poses a serious threat to genome integrity and greatly affects growth and development. To maintain genome stability, all organisms have evolved elaborate DNA damage response mechanisms including activation of cell cycle checkpoints and DNA repair. Here, we show that the DNA repair protein SNI1, a subunit of the evolutionally conserved SMC5/6 complex, directly links these two processes in Arabidopsis. SNI1 binds to the activation domains of E2F transcription factors, the key regulators of cell cycle progression, and represses their transcriptional activities. In turn, E2Fs activate the expression of SNI1, suggesting that E2Fs and SNI1 form a negative feedback loop. Genetically, overexpression of SNI1 suppresses the phenotypes of E2F-overexpressing plants, and loss of E2F function fully suppresses the sni1 mutant, indicating that SNI1 is necessary and sufficient to inhibit E2Fs. Altogether, our study revealed that SNI1 is a negative regulator of E2Fs and plays dual roles in DNA damage responses by linking cell cycle checkpoint and DNA repair.