ADAR1 promotes robust hypoxia signaling via distinct regulation of multiple HIF-1α-inhibiting factors.

Abstract:

:Adenosine deaminase acting on RNA (ADAR)-catalyzed adenosine-to-inosine RNA editing is potentially dysregulated in neoplastic progression. However, how this transcriptome recoding process is functionally correlated with tumorigenesis remains largely elusive. Our analyses of RNA editome datasets identify hypoxia-related genes as A-to-I editing targets. In particular, two negative regulators of HIF-1A-the natural antisense transcript HIF1A-AS2 and the ubiquitin ligase scaffold LIMD1-are directly but differentially modulated by ADAR1. We show that HIF1A-AS2 antagonizes the expression of HIF-1A in the immediate-early phase of hypoxic challenge, likely through a convergent transcription competition in cis ADAR1 in turn suppresses transcriptional progression of the antisense gene. In contrast, ADAR1 affects LIMD1 expression post-transcriptionally, by interfering with the cytoplasmic translocation of LIMD1 mRNA and thus protein translation. This multi-tier regulation coordinated by ADAR1 promotes robust and timely accumulation of HIF-1α upon oxygen depletion and reinforces target gene induction and downstream angiogenesis. Our results pinpoint ADAR1-HIF-1α axis as a hitherto unrecognized key regulator in hypoxia.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Ma CP,Liu H,Yi-Feng Chang I,Wang WC,Chen YT,Wu SM,Chen HW,Kuo YP,Shih CT,Li CY,Tan BC

doi

10.15252/embr.201847107

subject

Has Abstract

pub_date

2019-05-01 00:00:00

issue

5

eissn

1469-221X

issn

1469-3178

pii

embr.201847107

journal_volume

20

pub_type

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