MACROD2 haploinsufficiency impairs catalytic activity of PARP1 and promotes chromosome instability and growth of intestinal tumors
Details
Publication Year 2018, Volume 8, Issue #8, Page 988-1005
Journal Title
Cancer Discovery
Publication Type
Journal Article
Abstract
ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here we show that frequent deletions (~30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer (CRC) cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage, and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human CRC xenografts. MACROD2 deletion in sporadic CRC is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability thereby driving cancer evolution.
Publisher
AACR
WEHI Research Division(s)
Inflammation; Systems Biology And Personalised Medicine
PubMed ID
29880585
NHMRC Grants
NHMRC/1079364
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-06-26 12:34:41
Last Modified: 2018-09-25 09:29:14
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