HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs).
HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs).
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DOI：
10.18632/oncotarget.13807
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发表时间：
2017-01-10
期刊：
影响因子：
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通讯作者：
Leprince D
中科院分区：
文献类型：
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作者：
Paget S;Dubuissez M;Dehennaut V;Nassour J;Harmon BT;Spruyt N;Loison I;Abbadie C;Rood BR;Leprince D
肿瘤抑制基因SIRT 1（Hypermethylated In Cancer 1）编码一种转录抑制因子，通过SIRT 1的直接转录抑制介导对不可修复的DNA双链断裂（DSB）的p53依赖性凋亡反应。BJ-hTERT 1对于DSB修复也是必需的，因为在功能性彗星试验中，BJ-hTERT成纤维细胞中内源性BJ-hTERT 1的沉默显著延迟DNA修复。HIC 1 SUMO化有利于其与MTA 1（NuRD复合物的组分）相互作用。与依托泊苷治疗16小时诱导的不可修复的DSB相比，我们发现，1小时依托泊苷治疗诱导的可修复的DSB不增加α 1 SUMO化或其与MTA 1的相互作用。此外，由于在彗星试验中不可SUMO化的E316 A突变体与wt E316 A 1一样有效，因此E316 A 1 SUMO化对于DNA修复是无效的。在诱导不可修复的DSB后，ATM介导的EST 1 SUMO化的增加不依赖于其效应激酶Chk 2。此外，不可修复的DSB强烈增加了MTA 1和MTA 3的相互作用以及它们与SIRT 1启动子的结合。为了表征这种增加的抑制潜力所维持的分子机制，我们建立了用BJ-hTERT-siRNA或对照siRNA转染并用依托泊苷处理或不处理的BJ-hTERT成纤维细胞的全局表达谱。我们确定了475个基因潜在的抑制与细胞死亡和细胞周期作为主要的细胞功能，通过通路分析确定的BMP 1。其中，CXCL 12、EPHA 4、TGFβR3和TRIB 2（也称为MTA 1靶基因）通过qRT-PCR分析进行验证。因此，我们的数据表明，HIC 1 SUMO化对于不可修复的DSB的转录反应很重要，但对于DNA修复来说是可有可无的。
The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair.