Issues

Sakthianandeswaren, Parsons, Mouradov, and colleagues found that the MACROD2 locus, which encodes a mono-ADP-ribosylhydrolase implicated in the regulation of PARP1, undergoes recurrent focal deletions in a subset of human colorectal cancers. Consistent with a tumor-suppressive role, loss of MACROD2 increased the growth of intestinal tumors in mice in a haploinsufficient manner. This effect was mediated at least in part via repression of PARP1 activity in response to MACROD2 deletion, leading to impaired DNA repair and enhanced sensitivity to genotoxic stress. MACROD2 loss recapitulated the phenotype of PARP1 inhibitor treatment, including mitotic chromosome missegregation and increased structural and numerical chromosome abnormalities, suggesting that MACROD2 loss promotes chromosome instability and aneuploidy. These results define MACROD2 as a haploinsufficient tumor suppressor essential for maintaining genome integrity in human colorectal cancer. For details, please see the article by Sak thianandeswaren, Parsons, Mouradov, and colleagues on page 988.