Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors.

ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of enhances intestinal tumorigenesis in mice and the growth of human colorectal cancer xenografts. deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution. Chromosome instability (CIN) is a hallmark of cancer. We identify deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal as a major caretaker tumor suppressor gene. .