Fong Sylvia, King Frank, Shtivelman Emma
BioNovo Inc, 5858 Horton Street, Emeryville 94608, CA, USA.
BMC Cell Biol. 2010 Apr 7;11:23. doi: 10.1186/1471-2121-11-23.
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.
促凋亡蛋白CC3/TIP30具有一种不寻常的细胞功能，即作为核质运输的抑制剂。这种功能可能在应激条件下被激活。许多研究支持CC3在多种癌症中作为肿瘤和转移抑制因子的观点。CC3的酵母同源物可能参与对DNA损伤的反应。在此，我们研究了CC3在调节细胞对基因毒性应激反应中的潜在作用。
我们发现，在CC3阴性细胞中强制表达CC3会强烈延迟紫外线诱导的DNA损伤修复。外源导入的CC3会对DDB2/XPE和p21CIP1的表达水平产生负面影响，并抑制紫外线照射后c-FOS的诱导。此外，外源CC3会阻止紫外线照射后P21CIP的核积累。由CC3的强制表达导致的相关蛋白质水平/定位的这些变化可能导致观察到的DNA损伤修复延迟。在CC3阳性细胞中沉默CC3对紫外线诱导损伤的修复有适度的延迟作用，但对紫外线照射后的跨损伤DNA合成有更显著的负面影响。这可能与CC3表达被沉默的细胞中p21CIP1的较高表达水平和核定位增加有关。CC3的表达也会抑制氧化性DNA损伤的修复，并导致核氧化还原蛋白水平降低，这可能导致CC3表达细胞在氧化损伤后活力降低。
对细胞中CC3水平的调控会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。这会导致对基因毒性应激的反应改变，并通过影响将适量所需蛋白质募集到适当细胞区室而对DNA损伤修复产生不利影响。细胞中CC3过量对紫外线和氧化剂暴露后的DNA修复有显著负面影响，而内源性CC3的沉默会轻微延迟紫外线诱导损伤的修复。
