Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair.,Cell Reports

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Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair.
Cell Reports ( IF 7.5 ) Pub Date : 2018-10-09 , DOI: 10.1016/j.celrep.2018.09.022
Dan Wang ₁ , Rui Zhao ₂ , Yuan-Yuan Qu ₃ , Xin-Yu Mei ₂ , Xuan Zhang ₂ , Qian Zhou ₂ , Yang Li ₂ , Shao-Bo Yang ₄ , Zhi-Gui Zuo ₅ , Yi-Ming Chen ₆ , Yan Lin ₇ , Wei Xu ₈ , Chao Chen ₄ , Shi-Min Zhao ₈ , Jian-Yuan Zhao ₈

Affiliation

Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development and Children's Hospital of Fudan University, Shanghai 200438, China; Department of Neonatology and Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200438, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200438, China.
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development and Children's Hospital of Fudan University, Shanghai 200438, China.
Department of Neonatology and Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development and Children's Hospital of Fudan University, Shanghai 200438, China.
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, China; Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development and Children's Hospital of Fudan University, Shanghai 200438, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

Colorectal cancer (CRC) onset is profoundly affected by Western diet. Here, we report that high-fat (HF) diet-induced, organ-specific colonic lysine homocysteinylation (K-Hcy) increase might promote CRC onset by impeding DNA damage repair. HF chow induced elevated methionyl-tRNA synthetase (MARS) expression and K-Hcy levels and DNA damage accumulation in the mouse and rat colon, resulting in a phenotype identical to that of CRC tissues. Moreover, the increased copy number of MARS, whose protein product promotes K-Hcy, correlated with increased CRC risk in humans. Mechanistically, MARS preferentially bound to and modified ataxia-telangiectasia and Rad3-related protein (ATR), inhibited ATR and its downstream effectors checkpoint kinase-1 and p53, and relieved cell-cycle arrest and decreased DNA damage-induced apoptosis by disrupting the binding of ATR-interacting protein to ATR. Inhibiting K-Hcy by targeting MARS reversed these effects and suppressed oncogenic CRC cell growth. Our study reveals a mechanism of Western-diet-associated CRC and highlights an intervention approach for reversing diet-induced oncogenic effects.

中文翻译：

高脂饮食引起的结肠赖氨酸同型半胱氨酸化抑制DNA损伤修复。

西方饮食严重影响了大肠癌的发病。在这里，我们报道高脂饮食诱导的器官特异性结肠赖氨酸高半胱氨酸化（K-Hcy）增加可能通过阻止DNA损伤修复而促进CRC的发作。HF引起的甲硫氨酰-tRNA合成酶（MARS）表达和K-Hcy水平升高，并且在小鼠和大鼠结肠中积累了DNA损伤，导致其表型与CRC组织的表型相同。此外，其蛋白质产物促进K-Hcy的MARS拷贝数增加与人类CRC风险增加相关。从机制上讲，MARS优先结合并修饰了共济失调-毛细血管扩张和Rad3相关蛋白（ATR），抑制了ATR及其下游效应子Checkpoint激酶1和p53，通过破坏ATR相互作用蛋白与ATR的结合，减轻细胞周期停滞并减少DNA损伤诱导的细胞凋亡。通过靶向MARS抑制K-Hcy可逆转这些作用并抑制致癌CRC细胞的生长。我们的研究揭示了与西方饮食相关的CRC的机制，并强调了一种逆转饮食引起的致癌作用的干预方法。

更新日期：2018-10-11

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