Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer.
Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer.
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DOI：
10.1093/nar/gky162
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发表时间：
2018-05-18
影响因子：
14.9
通讯作者：
Doetsch PW
中科院分区：
文献类型：
--
作者：
Limpose KL;Trego KS;Li Z;Leung SW;Sarker AH;Shah JA;Ramalingam SS;Werner EM;Dynan WS;Cooper PK;Corbett AH;Doetsch PW
碱基切除修复（BER）是由DNA n -糖基化酶蛋白启动的，是修复潜在突变性DNA碱基损伤的第一线。NTHL1糖基酶可以去除活性氧引起的DNA碱基损伤，被认为是一种肿瘤抑制因子。然而，除了NTHL1功能缺失突变外，我们对癌症基因组数据集的分析显示，NTHL1在某些癌症中经常经历扩增或上调。NTHL1过表达是否有助于癌症表型尚未被探索。为了解决NTHL1过表达的功能后果，我们采用了瞬时过表达。当NTHL1和催化死亡的NTHL1 （CATmut）过表达时，在非转化的人支气管上皮细胞（HBEC）中都会诱导DNA损伤和基因组不稳定。引人注目的是，NTHL1或CATmut的过表达会导致复制应激信号和同源重组（HR）的减少。过表达NTHL1或CATmut的HBEC细胞获得了在软琼脂中生长的能力，并表现出接触抑制的丧失，这表明一种独立于NTHL1催化活性的机制有助于获得癌症相关的细胞表型。我们提供的证据表明，NTHL1与多功能DNA修复蛋白XPG相互作用，表明对HR的干扰可能是一种有助于获得癌症早期细胞特征的机制。
Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
3.7
作者：
Lin YF;Nagasawa H;Little JB;Kato TA;Shih HY;Xie XJ;Wilson PF Jr;Brogan JR;Kurimasa A;Chen DJ;Bedford JS;Chen BP
通讯作者：
Chen BP
影响因子：
14.9
作者：
Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
通讯作者：
Humphrey TC
影响因子：
4.8
作者：
Ikeda, S;Biswas, T;Mitra, S
通讯作者：
Mitra, S