<i>MACROD2</i> Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Abstract

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 <i>MACROD2</i> mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. <i>MACROD2</i> haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of <i>Macrod2</i> enhances intestinal tumorigenesis in <i>Apc</i>^Min/+ mice and the growth of human colorectal cancer xenografts. <i>MACROD2</i> 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 <i>MACROD2</i> acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.<b>Significance:</b> Chromosome instability (CIN) is a hallmark of cancer. We identify <i>MACROD2</i> deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. <i>MACROD2</i> haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal <i>MACROD2</i> as a major caretaker tumor suppressor gene. <i>Cancer Discov; 8(8); 988-1005. ©2018 AACR.</i><i>See related commentary by Jin and Burkard, p. 921</i><i>This article is highlighted in the In This Issue feature, p. 899</i>.