Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 15, Pages 7953-7969Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky396
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Funding
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- NMRC Clinician Scientist-Individual Research Grant New Investigator Grant (CS-IRG NIG) [NMRC/CNIG/1117/2014]
- NMRC Clinician Scientist-Individual Research Grant (CS-IRG) [NMRC/CIRG/1412/2014]
- NUS Young Investigator Award (NUS YIA) [NUSYIA_FY14_P22]
- NUS Start-up Fund [NUHSRO/2015/095/SU/01]
- Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award
- NIH/NCI Grant [R35CA197697]
- Singapore Ministry of Education's Tier 3 Grants [MOE2014-T3-1-006]
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Adenosine-to-inosine (A-to-I) RNA editing entails the enzymatic deamination of adenosines to inosines by adenosine deaminases acting on RNA (ADARs). Dysregulated A-to-I editing has been implicated in various diseases, including cancers. However, the precise factors governing the A-to-I editing and their physiopathological implications remain as a longstanding question. Herein, we unravel that DEAH box helicase 9 (DHX9), at least partially dependent of its helicase activity, functions as a bidirectional regulator of A-to-I editing in cancer cells. Intriguingly, the ADAR substrate specificity determines the opposing effects of DHX9 on editing as DHX9 silencing preferentially represses editing of ADAR1-specific substrates, whereas augments ADAR2-specific substrate editing. Analysis of 11 cancer types from The Cancer Genome Atlas (TCGA) reveals a striking overexpression of DHX9 in tumors. Further, tumorigenicity studies demonstrate a helicase-dependent oncogenic role of DHX9 in cancer development. In sum, DHX9 constitutes a bidirectional regulatory mode in A-to-I editing, which is in part responsible for the dysregulated editome profile in cancer.
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