Hypoxia-driven splicing into noncoding isoforms regulates the DNA damage response

Memon, D., Dawson, K., Smowton, C. S., Xing, W., Dive, C. and Miller, C. J. (2016) Hypoxia-driven splicing into noncoding isoforms regulates the DNA damage response. npj Genomic Medicine, 1, 16020. (doi: 10.1038/npjgenmed.2016.20) (PMID:28480052) (PMCID:PMC5417364)

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Abstract

Tumour hypoxia is associated with poor patient outcome and resistance to therapy. It is accompanied by widespread changes in gene expression mediated largely through the transcription factors HIF1/2/3α. Hypoxia impacts on multiple pathways throughout the cell and has widespread effects on phenotype. Here we use sample-specific annotation approaches to determine the changes in transcript architecture that arise as result of alternative splicing in hypoxic cells. Using in vivo data generated from a time course in reduced oxygenation we identified genome-wide switching between coding and noncoding isoforms, including a significant number of components of the DNA damage response pathway. Notably, HDAC6, a master regulator of the cytotoxic response, and TP53BP1, which sits at the nexus of the double-strand break repair pathway, both underwent a marked transition towards an intron-retention pattern with a concomitant decline in protein levels. These transitions from coding to noncoding isoforms were recapitulated in a large and independent cohort of 499 colorectal samples taken from The Cancer Genome Atlas (TCGA). The set of altered genes was enriched for multiple components of the Fanconi Anaemia, nucleotide excision and double-strand break repair pathways, and together correlating with tumour status at last contact. Altogether, these data demonstrate a new role for hypoxia-driven alternative splicing in regulating DNA damage response, and highlight the importance of considering alternative splicing as a critical factor in our understanding of human disease.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK (Grant number: C5759/A12328).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Professor Crispin
Authors: Memon, D., Dawson, K., Smowton, C. S., Xing, W., Dive, C., and Miller, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:npj Genomic Medicine
Publisher:Nature Research
ISSN:2056-7944
ISSN (Online):2056-7944
Copyright Holders:Copyright © The Author(s) 2016
First Published:First published in npj Genomic Medicine 1:16020
Publisher Policy:Reproduced under a Creative Commons Licence

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