Cellular dynamics and modulation of WRN protein is DNA damage specific
Cellular dynamics and modulation of WRN protein is DNA damage specific
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DOI：
10.1016/j.mad.2005.06.004
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Bohr, VA
中科院分区：
文献类型：
--
作者：
Karmakar, P;Bohr, VA
人早衰蛋白Werner（WRN）在Werner综合征（WS）中缺乏，主要定位于许多细胞类型的核仁。DNA损伤或复制停滞导致WRN从核仁到核质重新分布成离散的病灶。在这项研究中，我们研究了WRN的DNA损伤特异性细胞再分布。为了响应引起DNA双链断裂或DNA碱基损伤的试剂，WRN以可逆的方式从核仁重新分布到核质。然而，在紫外线（UV）照射后，WRN的这种重新分布基本上是不存在的。我们还表明，WRN与细胞暴露于各种DNA损伤后的不溶性蛋白质部分有关，但在紫外线照射后不相关。此外，我们还研究了WRN的DNA损伤特异性翻译后调节。我们的研究结果表明，WRN乙酰化后丝裂霉素C或甲基磺酸甲酯的处理，但不经紫外线照射。此外，DNA损伤特异性磷酸化的WRN是不存在的UV照射的细胞。抑制磷酸化不能恢复WRN定位。因此，我们的研究结果表明，WRN蛋白运输的动力学是DNA损伤特异性的，并与其翻译后调制。结果还表明WRN在重组和碱基切除修复中的优选作用，而不是核苷酸切除修复。出版社：Elsevier爱尔兰Ltd.
The human premature aging protein Werner (WRN), deficient in Werner syndrome (WS), is localized mainly to the nucleolus in many cell types. DNA damage or replication arrest causes WRN to redistribute from the nucleolus to the nucleoplasm into discrete foci. In this study, we have investigated DNA damage specific cellular redistribution of WRN. In response to agents causing DNA double strand breaks or DNA base damage, WRN is re-distributed from the nucleolus to the nucleoplasm in a reversible manner. However, after ultraviolet (UV) irradiation such redistribution of WRN is largely absent. We also show that WRN is associated with the insoluble protein fraction of cells after exposure to various kinds of DNA damage but not after UV irradiation. Further, we have studied the DNA damage specific post-translational modulation of WRN. Our results show that WRN is acetylated after mytomycin C or methyl methane-sulfonate treatment, but not after UV irradiation. Also, DNA damage specific phosphorylation of WRN is absent in UV irradiated cells. Inhibition of phosphorylation fails to restore WRN localization. Thus, our results suggest that the dynamics of WRN protein trafficking is DNA damage specific and is related to its post-translational modulation. The results also indicate a preferred role of WRN in recombination and base excision repair rather than nucleotide excision repair. Published by Elsevier Ireland Ltd.