Abstract：
: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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Wang D,Zhao R,Qu YY,Mei XY,Zhang X,Zhou Q,Li Y,Yang SB,Zuo ZG,Chen YM,Lin Y,Xu W,Chen C,Zhao SM,Zhao JYdoi
10.1016/j.celrep.2018.09.022subject
Has Abstractpub_date
2018-10-09 00:00:00pages
398-412.e6issue
2issn
2211-1247pii
S2211-1247(18)31452-9journal_volume
25pub_type
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