Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18127
Title: MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors.
Authors: Sakthianandeswaren, Anuratha;Parsons, Marie J;Mouradov, Dmitri;MacKinnon, Ruth N;Catimel, Bruno;Liu, Sheng;Palmieri, Michelle;Love, Christopher;Jorissen, Robert N;Li, Shan;Whitehead, Lachlan;Putoczki, Tracy L;Preaudet, Adele;Tsui, Cary;Nowell, Cameron J;Ward, Robyn L;Hawkins, Nicholas J;Desai, Jayesh;Gibbs, Peter;Ernst, Matthias;Street, Ian;Buchert, Michael;Sieber, Oliver M
Affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
Victorian Cancer Cytogenetics Service, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
Department of Medicine, The University of Melbourne (St Vincent's Hospital), Fitzroy, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Department of Pathology, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Histology Facility, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Drug Discovery Biology, The Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Office of the Deputy Vice-Chancellor (Research), The University of Queensland, Brisbane, Queensland, Australia
Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia
Olivia Newton John Cancer Wellness and Research Centre, Austin Health, Heidelberg, Victoria, Australia
School of Cancer Medicine, LaTrobe University, Heidelberg, Victoria, Australia
Cancer Therapeutics Cooperative Research Centre, Parkville, Victoria, Australia
Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: Aug-2018
EDate: 2018-06-07
Citation: Cancer discovery 2018; 8(8): 988-1005
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18127
DOI: 10.1158/2159-8290.CD-17-0909
ORCID: 0000-0003-0294-5051
0000-0002-6399-1177
PubMed URL: 29880585
Type: Journal Article
Appears in Collections:Journal articles

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