CC3/TIP30 affects DNA damage repair.
CC3/TIP30 affects DNA damage repair.
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DOI：
10.1186/1471-2121-11-23
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发表时间：
2010-04-07
期刊：
影响因子：
--
通讯作者：
Shtivelman E
中科院分区：
文献类型：
--
作者：
Fong S;King F;Shtivelman E
促凋亡蛋白CC 3/TIP 30作为核质转运的抑制剂具有不寻常的细胞功能。这种功能在压力条件下可能被激活。许多研究支持CC 3在各种类型的癌症中作为肿瘤和转移抑制因子的观点。CC 3的酵母同系物可能参与对DNA损伤的反应。在这里，我们研究了CC 3在调节细胞对遗传毒性应激反应中的潜在作用。我们发现在CC 3阴性细胞中强制表达CC 3强烈延迟UV诱导的DNA损伤的修复。外源性CC 3对DDB 2/XPE和p21 CIP 1的表达水平有负面影响，并抑制紫外线照射后c-FOS的诱导。此外，外源性CC 3阻止了P21 CIP在细胞核中的积累。由CC 3的强制表达引起的相关蛋白质的水平/定位的这些变化可能有助于观察到的DNA损伤修复的延迟。CC 3阳性细胞中CC 3的沉默对UV诱导的损伤的修复具有适度的延迟作用，但对UV暴露后的跨损伤DNA合成具有更显著的负面影响。这可能与CC 3表达沉默的细胞中p21 CIP 1的较高表达水平和增加的核定位有关。CC 3的表达还抑制氧化性DNA损伤的修复，并导致核氧还蛋白水平的降低，这可能导致氧化损伤后表达CC 3的细胞的活力降低。CC 3的细胞水平的操纵改变表现出核质穿梭的蛋白质的表达水平和/或亚细胞定位。这导致对遗传毒性应激的反应改变，并通过影响向适当的细胞区室募集足够量的所需蛋白质而对DNA损伤修复产生不利影响。过量的细胞CC 3对UV和氧化剂暴露后的DNA修复具有显著的负面影响，而内源性CC 3的沉默略微延迟UV诱导的损伤的修复。
The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress. We found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult. Manipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.
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DOI：
10.1083/jcb.133.1.211
发表时间：
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期刊：
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影响因子：
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DOI：
10.1073/pnas.0511160103
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2006-02-21
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