CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage.
CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage.
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DOI：
10.1093/nar/gks222
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发表时间：
2012-07
影响因子：
14.9
通讯作者：
Hendzel MJ
中科院分区：
文献类型：
--
作者：
Ismail IH;Gagné JP;Caron MC;McDonald D;Xu Z;Masson JY;Poirier GG;Hendzel MJ
聚梳组(Polycomb group，PcG)蛋白参与表观遗传沉默，在表观遗传沉默中，它们作为细胞特性、干细胞多能性和参与癌症发展的表观遗传基因沉默的主要决定因素发挥作用。最近，大量的PcG蛋白，包括CBX4，已经被证明在DNA损伤的位置积聚。然而，目前尚不清楚CBX4或其E3相扑连接酶活性是否直接参与了DNA损伤反应(DDR)。在这里，我们定义了CBX4作为一种早期DDR蛋白的新角色，它介导DNA损伤部位的相扑结合。DNA损伤刺激CBX4在赖氨酸88位激活BMI1，这是BMI1在DNA损伤部位积累所必需的。此外，我们建立了CBX4在激光微照射诱导的DNA损伤部位的募集需要PARP活性，而不需要H_2AX、RNF8、BMI1或PI-3相关的激酶。CBX4的缺失证实了CBX4在DDR中的重要性，CBX4导致细胞对电离辐射的抵抗力降低。我们的结果揭示了CBX4在DDR途径中的直接作用。
Polycomb group (PcG) proteins are involved in epigenetic silencing where they function as major determinants of cell identity, stem cell pluripotency and the epigenetic gene silencing involved in cancer development. Recently numerous PcG proteins, including CBX4, have been shown to accumulate at sites of DNA damage. However, it remains unclear whether or not CBX4 or its E3 sumo ligase activity is directly involved in the DNA damage response (DDR). Here we define a novel role for CBX4 as an early DDR protein that mediates SUMO conjugation at sites of DNA lesions. DNA damage stimulates sumoylation of BMI1 by CBX4 at lysine 88, which is required for the accumulation of BMI1 at DNA damage sites. Moreover, we establish that CBX4 recruitment to the sites of laser micro-irradiation-induced DNA damage requires PARP activity but does not require H2AX, RNF8, BMI1 nor PI-3-related kinases. The importance of CBX4 in the DDR was confirmed by the depletion of CBX4, which resulted in decreased cellular resistance to ionizing radiation. Our results reveal a direct role for CBX4 in the DDR pathway.
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影响因子：
4.3
作者：
Gieni, Randall S.;Ismail, Ismail H.;Hendzel, Michael J.
通讯作者：
Hendzel, Michael J.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.9
作者：
Gieni, Randall S.;Hendzel, Michael J.
通讯作者：
Hendzel, Michael J.
DOI：
10.1073/pnas.1014263108
发表时间：
2011-03-29
影响因子：
11.1
作者：
Chagraoui, Jalila;Hebert, Josee;Sauvageau, Guy
通讯作者：
Sauvageau, Guy
影响因子：
4.4
作者：
Gagne, Jean-Philippe;Moreel, Xavier;Poirier, Guy G.
通讯作者：
Poirier, Guy G.