Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes.
Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes.
复制标题
DOI：
10.1002/em.22074
复制
发表时间：
2017-03
影响因子：
2.8
通讯作者：
Wilson DM 3rd
中科院分区：
文献类型：
--
作者：
Illuzzi JL;McNeill DR;Bastian P;Brenerman B;Wersto R;Russell HR;Bunz F;McKinnon PJ;Becker KG;Wilson DM 3rd
碱基切除修复（BER）是应对大多数形式的内源性DNA损伤的主要途径，并且该过程中的缺陷与癌症发生有关。脱嘌呤/脱嘧啶核酸内切酶1（Apurinic/apyrimidinic endonuclease 1，APE 1）是BER的核心参与者，在DNA非编码脱碱基位点的加工中起着关键的内切酶作用。有证据表明，APE 1错义突变体以及蛋白质表达或定位的改变可能导致疾病表现。我们在此报告，肿瘤相关的APE 1变体，R237 C，显示出降低的甲磺酸甲酯超敏反应的互补效率和APE 1缺陷小鼠胚胎成纤维细胞表现出的细胞生长受损。野生型APE 1或R237 C变体在非转化的C127 I小鼠细胞系中的过表达对增殖、细胞周期状态、稳态DNA损伤水平、线粒体功能或细胞转化没有影响。APE 1敲除等位基因杂合子的人细胞系内源性APE 1水平较低，细胞对DNA损伤剂的敏感性增加，增殖随时间推移受损，并且具有与应激表型一致的独特的全局基因表达模式。我们的研究结果表明：（i）肿瘤相关的R237 C变体是一种可能的易感因子，但不太可能是癌细胞表型的驱动因素，（ii）APE 1的过表达不容易促进细胞转化，（iii）APE 1基因座的单倍不足可能具有深远的细胞后果，与BER在细胞增殖中发挥关键作用一致。
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of non-coding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the non-transformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells.