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MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

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MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 RESEARCH ARTICLE MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors Anuratha Sakthianandeswaren1,2, Marie J. Parsons1,3, Dmitri Mouradov1,2, Ruth N. MacKinnon4,5, Bruno Catimel1,2, Sheng Liu1,2, Michelle Palmieri1,2, Christopher Love6, Robert N. Jorissen1,2, Shan Li1, Lachlan Whitehead1,2, Tracy L. Putoczki2,7, Adele Preaudet7, Cary Tsui8, Cameron J. Nowell9, Robyn L. Ward10, Nicholas J. Hawkins11, Jayesh Desai1,2,12, Peter Gibbs1,2,12, Matthias Ernst13,14, Ian Street1,2,15, Michael Buchert13,14, and Oliver M. Sieber1,2,3,16 ABSTRACT ADP-ribosylation is an important posttranslational protein modification that regu- lates diverse biological processes, controlled by dedicated transferases and hydro- lases. 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 dele- tion 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 haploin- sufficient 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); 1–18. ©2018 AACR. See related commentary by Jin and Burkard, p. 921. 1Systems Biology and Personalised Medicine Division, The Walter and Australia. 13Olivia Newton-John Cancer Research Institute, Olivia Newton- Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. John Cancer & Wellness Centre, Heidelberg, Victoria, Australia. 14School 2Department of Medical Biology, The University of Melbourne, Parkville, of Cancer Medicine, LaTrobe University, Heidelberg, Victoria, Australia. Victoria, Australia. 3Department of Surgery, The University of Melbourne, 15Cancer Therapeutics Cooperative Research Centre, Parkville, Victoria, Parkville, Victoria, Australia. 4Victorian Cancer Cytogenetics Service, St Australia. 16Department of Biochemistry & Molecular Biology, Monash Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia. 5Department University, Clayton, Victoria, Australia. of Medicine, The University of Melbourne (St Vincent’s Hospital), Fitzroy, Note: Supplementary data for this article are available at Cancer Discovery 6 Victoria, Australia. Department of Pathology, Peter MacCallum Cancer Online (http://cancerdiscovery.aacrjournals.org/). Centre, Parkville, Victoria, Australia. 7Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. A. Sakthianandeswaren, M.J. Parsons, and D. Mouradov contributed equally 8Histology Facility, The Walter and Eliza Hall Institute of Medical Research, to this article. Parkville, Victoria, Australia. 9Drug Discovery Biology, The Monash Insti- Corresponding Author: Oliver M. Sieber, The Walter and Eliza Hall Institute tute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Australia. 10Office of the Deputy Vice-Chancellor (Research), The Univer- Phone: 613-9345-2885. E-mail: [email protected] 11 sity of Queensland, Brisbane, Queensland, Australia. Faculty of Medicine, doi: 10.1158/2159-8290.CD-17-0909 The University of Queensland, Brisbane, Queensland, Australia. 12Depart- ment of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, ©2018 American Association for Cancer Research. OF1 | CANCER DISCOVERY AUGUST 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 MACROD2 Loss Impairs PARP1 Activity and Promotes CIN in Colorectal Cancer RESEARCH ARTICLE INTRODUCTION establishes and amplifies the DNA-damage signal, recruiting repair factors and activating effector proteins involved in the ADP-ribosylation is a widespread posttranslational pro- DNA-damage response, including master regulators such tein modification at DNA lesions, which is governed by the as ATM, ATR, and DNA-dependent protein kinase (8). PAR activities of specific transferases and hydrolases. This modifi- synthesis is reversed by degradation by poly(ADP-ribose) cation regulates various biological processes, including DNA- glycohydrolase; however, removal of the terminal autoinhibi- damage response, chromatin reorganization, transcriptional tory mono-ADP-ribose from PARP1 to cause reactivation regulation, apoptosis, and mitosis (1–3). Genome-wide DNA requires MACROD2 recruitment and enzymatic activity (7). copy-number analyses across human cancers have revealed MACROD2 phosphorylation by ATM acts as a negative feed- common focal deletions of the MACROD2 mono-ADP- back loop, triggering MACROD2 nuclear export upon DNA ribosylhydrolase locus on chromosome 20p12.1 in multiple damage, thus temporally restricting its recruitment to DNA malignancies, including gastric and colorectal cancers (4, 5). lesions (9). However, the locus is considered a tissue-specific fragile site MACROD2 has further been implicated as a regulator of (6), and whether MACROD2 aberrations contribute to car- glycogen synthase kinase 3-beta (GSK3β), indicating a role in cinogenesis is unknown. the modulation of WNT signaling (10). MACROD2 reverses Recent studies have identified MACROD2 as a regulator PARP10-catalyzed mono-ADP-ribose-mediated inhibition of of PARP1, a principal sensor of DNA single-strand breaks GSK3β, activating GSK3β to phosphorylate β-catenin in the (SSB) and double-strand breaks (DSB; ref. 7). Following context of a protein complex with adenomatous polyposis coli binding to sites of DNA nicks or breaks, PARP1 polymer- (APC), axin, and other components. Phosphorylation targets izes PAR chains onto histones and other proteins, includ- β-catenin for ubiquitination and proteasomal degradation, ing itself. This auto- and substrate-PARylation by PARP1 preventing its translocation to the nucleus and interaction AUGUST 2018 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 RESEARCH ARTICLE Sakthianandeswaren et al. with members of the T-cell factor/lymphoid enhancer factor microdeletions also exhibited aberrant MACROD2 tran- (TCF/LEF) transcription factor family to activate expression scripts lacking one or more exons, indicating pathogenicity of WNT target genes (11). in these cases. In five cell lines with multiple heterozygous These observations raise the possibility that somatic exonic or intronic MACROD2 aberrations, no wild-type tran- genomic aberrations in MACROD2 contribute to cancer devel- script was detected consistent with deletions affecting both opment through impairing the DNA-damage response or alleles. Aberrant transcripts were predicted to result in pre- promoting aberrant WNT signaling. Here, we present genetic, mature MACROD2 protein truncation in 28% (7 of 26) of biochemical, and functional data that reveal MACROD2 as cases, or in-frame exonic deletions involving the catalytic a caretaker tumor suppressor gene essential for the mainte- macrodomain of the protein in 72% (19 of 26) of cases (Sup- nance of cancer genome integrity. plementary Table S4). MACROD2 Somatic Mutation Burden in Human RESULTS Colorectal Cancer Focal Deletions at Chromosome 20p12.1 Target We next examined the contribution of somatic mutations MACROD2 in Human Colorectal Cancer to the burden of MACROD2 aberrations in colorectal cancer. To comprehensively characterize the human cancer types We sequenced all exons of MACROD2 in 102 sporadic colorec- in which the MACROD2 locus is subject to focal deletions tal cancers and 53 colorectal cancer cell lines. Detected vari- at chromosome 20p12.1, we analyzed The Cancer Genome ants were verified to not correspond to known SNPs, and for Atlas (TCGA)–derived DNA copy-number data from 10,575 primary tumors were confirmed to be somatically acquired by tumors representing 32 malignancies using Genomic Iden- sequencing of matched normal tissue. Results were combined tification of Significant Targets in Cancer (GISTIC; ref. with TCGA-derived mutation data for colorectal cancer (n = 12). Colorectal adenocarcinoma (COAD/READ) exhibited 536; Supplementary Table S5). the strongest evidence for recurrent focal DNA copy-num- Somatic MACROD2 mutations were found to be of low ber loss at MACROD2 (q = 5.89E−78), but targeting was prevalence, with 14 missense mutations detected in a total also observed in stomach adenocarcinoma (STAD), cervical of 691 cases. MACROD2 missense mutations were localized squamous cell carcinoma and endocervical
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