Distinct functions for WRN and TP53 in a shared pathway of cellular response to 1-beta-D-arabinofuranosylcytosine and bleomycin.
Distinct functions for WRN and TP53 in a shared pathway of cellular response to 1-beta-D-arabinofuranosylcytosine and bleomycin.
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WRN 和 TP53 在细胞对 1-β-D-阿拉伯呋喃糖基胞嘧啶和博莱霉素反应的共享途径中具有不同的功能。
DOI：
10.1016/j.yexcr.2004.02.011
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发表时间：
2004
影响因子：
3.7
通讯作者：
Rabinovitch,PeterS
中科院分区：
文献类型：
--
作者：
Poot,Martin;Jin,Xiaoyang;Hill,JulianeP;Gollahon,KatherineA;Rabinovitch,PeterS
WRN或TP53基因的突变导致自发的遗传不稳定，肿瘤形成的风险增加，以及对干扰DNA复制的化合物（如喜树碱和DNA链间交联药物）的敏感性。我们通过将WRN缺陷和TP53突变淋巴母细胞样细胞系（LCLs）暴露于1-β-d-阿拉伯糖核苷（AraC）和博来霉素，研究了WRN和TP53参与DNA复制阻断病变的细胞反应的假设。在AraC和博来霉素的作用下，WRN或TP53功能的丧失导致细胞凋亡和较低的增殖生存。WRN和TP53在一个共享的DNA损伤应答通路中工作，因为在SV-40转化使TP53失活的细胞中，无论WRN状态如何，AraC和博来霉素的敏感性都没有差异。与TP53突变型LCLs相比，WRN缺陷细胞在AraC和博来霉素暴露后不受细胞周期阻滞的影响，这表明WRN不参与DNA损伤激活的细胞周期阻滞。WRN和TP53缺乏均不影响暴露于AraC和博来霉素后的细胞恢复，这与这些DNA损伤的直接修复作用不一致。我们的研究结果表明，WRN和TP53在共享的DNA损伤反应途径中发挥不同的功能。
Mutations in the WRN or the TP53 genes lead to spontaneous genetic instability, an elevated risk of tumor formation, and sensitivity to compounds that interfere with DNA replication, such as camptothecin and DNA interstrand cross-linking drugs. We investigated the hypothesis that WRN and TP53 are involved in cellular responses to DNA replication-blocking lesions by exposing WRN deficient and TP53 mutant lymphoblastoid cell lines (LCLs) to 1-β-d-arabinofuranosylcytosine (AraC) and bleomycin. Loss of WRN or TP53 function resulted in induction of apoptosis and lesser proliferative survival in response to AraC and bleomycin. WRN and TP53 operate in a shared DNA damage response pathway, since in cells in which TP53 was inactivated by SV-40 transformation, no difference in AraC and bleomycin sensitivity was found regardless of WRN status. In contrast to TP53 mutant LCLs, WRN-deficient cells showed unaffected cell cycle arrest after AraC and bleomycin exposure, which indicates that WRN is not involved in DNA damage-activated cell cycle arrest. Neither WRN nor TP53 deficiency affected cellular recovery from exposure to AraC and bleomycin, which disagrees with a direct role in repair of these DNA lesions. Our results indicate that WRN and TP53 perform different functions in a shared DNA damage response pathway.