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 MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer 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 colorectal cancer xenografts. MACROD2 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 MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988-1005. ©2018 AACR.See related commentary by Jin and Burkard, p. 921This article is highlighted in the In This Issue feature, p. 899.
Highlights
ADP-ribosylation is a widespread posttranslational protein modification at DNA lesions, which is governed by the activities of specific transferases and hydrolases
To comprehensively characterize the human cancer types in which the MACROD2 locus is subject to focal deletions at chromosome 20p12.1, we analyzed The Cancer Genome Atlas (TCGA)–derived DNA copy-number data from 10,575 tumors representing 32 malignancies using Genomic Identification of Significant Targets in Cancer
A similar deletion spectrum was observed for a panel of 53 human colorectal cancer cell lines, with validation of detected homozygous exonic MACROD2 deletions by the absence of reads in whole-exome sequencing (WES) data (Fig. 1C)
Summary
ADP-ribosylation is a widespread posttranslational protein modification at DNA lesions, which is governed by the activities of specific transferases and hydrolases This modification regulates various biological processes, including DNAdamage response, chromatin reorganization, transcriptional regulation, apoptosis, and mitosis [1,2,3]. Following binding to sites of DNA nicks or breaks, PARP1 polymerizes PAR chains onto histones and other proteins, including itself. This auto- and substrate-PARylation by PARP1 establishes and amplifies the DNA-damage signal, recruiting repair factors and activating effector proteins involved in the DNA-damage response, including master regulators such as ATM, ATR, and DNA-dependent protein kinase [8]. MACROD2 phosphorylation by ATM acts as a negative feedback loop, triggering MACROD2 nuclear export upon DNA damage, temporally restricting its recruitment to DNA lesions [9]
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