DNA Double-strand Breaks Lead to Activation of Hypermethylated in Cancer 1 (HIC1) by SUMOylation to Regulate DNA Repair
DNA Double-strand Breaks Lead to Activation of Hypermethylated in Cancer 1 (HIC1) by SUMOylation to Regulate DNA Repair
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DOI：
10.1074/jbc.m112.421610
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发表时间：
2013-04-12
影响因子：
4.8
通讯作者：
Leprince, Dominique
中科院分区：
文献类型：
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作者：
Dehennaut, Vanessa;Loison, Ingrid;Leprince, Dominique
HM 1（hypermethylated in cancer 1）是一种在人类癌症中经常表观遗传沉默的肿瘤抑制基因。BMP 1编码一个转录抑制因子，参与生长控制和DNA损伤反应的调节。我们以前证明，RISK 1可以乙酰化或SUMO化赖氨酸314。这种去乙酰化/SUMO化开关由SIRT 1和HDAC 4组成的不寻常的复合物控制，该复合物通过一种尚未完全破译的机制去乙酰化，从而有利于SIRT 1的SUMO化。这个开关调节MTA 1与MTA 1的相互作用，MTA 1是NuRD复合物的一个组分，并增强MTA 1的阻遏活性。在这里，我们表明，在人成纤维细胞中的H2 AX 1沉默影响DNA双链断裂的修复，而野生型H2 AX 1的异位表达，但不是nonsumoylatable突变体，导致依托泊苷治疗诱导的γ H2 AX病灶的数量减少。通过这种方式，我们证明了DNA损伤导致（i）增强的HDAC 4/Ubc 9相互作用，（ii）通过SUMO化（Lys-734）激活SIRT 1，以及（iii）SIRT 1对HDAC 4的SUMO依赖性募集，这允许HDAC 1的脱乙酰化/SUMO化开关。最后，我们发现，这种增加的SUMO化有利于EST 1/MTA 1的相互作用，从而表明，EST 1调节DNA修复的SUMO依赖的方式。因此，表观遗传学的α 1失活，这是肿瘤发生的早期步骤，可以通过受损的DNA修复促进DNA突变的积累，从而有利于肿瘤的发生。
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene frequently epigenetically silenced in human cancers. HIC1 encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that HIC1 can be either acetylated or SUMOylated on lysine 314. This deacetylation/SUMOylation switch is governed by an unusual complex made up of SIRT1 and HDAC4 which deacetylates and thereby favors SUMOylation of HIC1 by a mechanism not yet fully deciphered. This switch regulates the interaction of HIC1 with MTA1, a component of the NuRD complex and potentiates the repressor activity of HIC1. Here, we show that HIC1 silencing in human fibroblasts impacts the repair of DNA double-strand breaks whereas ectopic expression of wild-type HIC1, but not of nonsumoylatable mutants, leads to a reduced number of gamma H2AX foci induced by etoposide treatment. In this way, we demonstrate that DNA damage leads to (i) an enhanced HDAC4/Ubc9 interaction, (ii) the activation of SIRT1 by SUMOylation (Lys-734), and (iii) the SUMO-dependent recruitment of HDAC4 by SIRT1 which permits the deacetylation/SUMOylation switch of HIC1. Finally, we show that this increase of HIC1 SUMOylation favors the HIC1/MTA1 interaction, thus demonstrating that HIC1 regulates DNA repair in a SUMO-dependent way. Therefore, epigenetic HIC1 inactivation, which is an early step in tumorigenesis, could contribute to the accumulation of DNA mutations through impaired DNA repair and thus favor tumorigenesis.