The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation.
The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation.
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FEN1 L209P 突变干扰长补丁碱基切除修复并诱导细胞转化
作者：
Flap 核酸内切酶-1 (FEN1) 是一种多功能、结构特异性核酸酶，在维持人类基因组稳定性方面发挥着关键作用。 FEN1 突变已在人类癌症样本中检测到，并被认为会导致基因组不稳定和癌症易感性。然而，FEN1 缺乏与癌症易感性之间的确切关系仍不清楚。在当前的工作中，我们报告了一种新的结直肠癌相关 FEN1 突变 L209P。该突变蛋白缺乏 FEN1 的 FEN、核酸外切酶 (EXO) 和间隙核酸内切酶 (GEN) 活性，但保留了 DNA 结合亲和力。 L209P FEN1 变体以显性失活方式干扰野生型 FEN1 酶的功能，并在体外和体内损害长补丁碱基切除修复。 L209P FEN1 的表达使细胞对 DNA 损伤敏感，导致内源性基因组不稳定和细胞转化，以及小鼠异种移植模型中的肿瘤生长。这些数据表明，FEN1 基因中与人类癌症相关的遗传改变可能对癌症的发展产生重大影响。
Flap endonuclease-1 (FEN1) is a multifunctional, structure-specific nuclease that has a critical role in maintaining human genome stability. FEN1 mutations have been detected in human cancer specimens and have been suggested to cause genomic instability and cancer predisposition. However, the exact relationship between FEN1 deficiency and cancer susceptibility remains unclear. In the current work, we report a novel colorectal cancer-associated FEN1 mutation, L209P. This mutant protein lacks the FEN, exonuclease (EXO) and gap endonuclease (GEN) activities of FEN1 but retains DNA-binding affinity. The L209P FEN1 variant interferes with the function of the wild-type FEN1 enzyme in a dominant-negative manner and impairs long-patch base excision repair in vitro and in vivo. Expression of L209P FEN1 sensitizes cells to DNA damage, resulting in endogenous genomic instability and cellular transformation, as well as tumor growth in a mouse xenograft model. These data indicate that human cancer-associated genetic alterations in the FEN1 gene can contribute substantially to cancer development.
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影响因子：
5.3
作者：
Figueroa, Jonine D.;Malats, Nuria;Garcia-Closas, Montserrat
通讯作者：
Garcia-Closas, Montserrat
影响因子：
4.8
作者：
Frank, G;Qiu, JH;Shen, BH
通讯作者：
Shen, BH
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
5.3
作者：
Guo, Zhigang;Qian, Limin;Shen, Binghui
通讯作者：
Shen, Binghui
影响因子：
8
作者：
Henneke, G;Koundrioukoff, S;Hübscher, U
通讯作者：
Hübscher, U