Journal article
MACROD2 haploinsufficiency impairs catalytic activity of PARP1 and promotes chromosome instability and growth of intestinal tumors
A Sakthianandeswaren, MJ Parsons, D Mouradov, RN Mackinnon, B Catimel, S Liu, M Palmieri, C Love, RN Jorissen, S Li, L Whitehead, TL Putoczki, A Preaudet, C Tsui, CJ Nowell, RL Ward, NJ Hawkins, J Desai, P Gibbs, M Ernst Show all
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2018
Abstract
ADP-ribosylation is an important posttranslational protein modification that regulates 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 deletion in sporadic colorectal cancer is associated with..
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Awarded by Ludwig Institute for Cancer Research
Funding Acknowledgements
The authors thank the Victorian Cancer Biobank and BioGrid Australia for provision of patient specimens and data, and Prof. M. Schwab at the DKFZ for access to colorectal cancer cell lines. This work was supported by an NHMRC Project Grant (APP1079364 to O.M. Sieber, M. Buchert, J. Desai, and I. Street), a Cancer Council Victoria Grant-in-Aid (APP1060964 to O.M. Sieber and R.L. Ward), the Ludwig Institute for Cancer Research (O.M. Sieber), the Cancer Therapeutics Cooperative Research Centre (I. Street), an NHMRC Senior Research Fellowship (APP1136119 to O.M. Sieber), a Cancer Therapeutics CRC Top Up PhD Scholarship (M. J. Parsons), and the Victorian Government's Operational Infrastructure Support Program (O.M. Sieber).