1. Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
- Author
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Lana M. Pollock, Charles Vinson, Jennifer T. Fox, Kirk J. McManus, Hassan Mohamed, Nancy F. Hansen, Bhavesh Borate, Nisc Comparative Sequencing Program, Philip Hieter, Pedro Cruz, Maria J. Merino, Abdel G. Elkahloun, Masamichi Ishiai, Payal Sipahimalani, Christin L. Hanigan, Jessica C. Price, Praveen F. Cherukuri, Gene Elliot, Sarah Fogoros, Suiyuan Zhang, Raghunath Chatterjee, Jan Stoepel, Tyra G. Wolfsberg, Dae-Sik Lim, KS Lee, Dennis C. Sgroi, Kyungjae Myung, Minoru Takata, Nilabja Sikdar, Gabriel Renaud, Meghan L. Rudd, James C. Mullikin, Andrew K. Godwin, Daphne W. Bell, and Hee-Dong Park
- Subjects
Male ,Genome instability ,Cancer Research ,Somatic cell ,Aneuploidy ,medicine.disease_cause ,Mice ,Molecular cell biology ,0302 clinical medicine ,Neoplasms ,Genetics (clinical) ,Adenosine Triphosphatases ,0303 health sciences ,3. Good health ,Nucleic acids ,DNA-Binding Proteins ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Female ,Research Article ,lcsh:QH426-470 ,DNA damage ,Nonsense mutation ,DNA repair ,Biology ,Genomic Instability ,Cell Line ,03 medical and health sciences ,Germline mutation ,Proliferating Cell Nuclear Antigen ,Cancer Genetics ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Ubiquitination ,DNA ,medicine.disease ,Molecular biology ,Endometrial Neoplasms ,Proliferating cell nuclear antigen ,lcsh:Genetics ,Mutation ,biology.protein ,ATPases Associated with Diverse Cellular Activities ,Carcinogenesis ,DNA Damage - Abstract
ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis., Author Summary Genomic instability is a hallmark of tumorigenesis, suggesting that mutations in genes suppressing genomic instability contribute to this phenotype. In this study, we demonstrate for the first time that haploinsufficiency for Atad5, a protein that is important in stabilizing stalled DNA replication forks by regulating PCNA ubiquitination during DNA damage bypass, predisposes >90% of mice to tumorigenesis in multiple organs. In heterozygous Atad5 mice, both somatic cells and the spontaneous tumors showed high levels of genomic instability. In a subset of sporadic human endometrial tumors, we identified heterozygous loss-of-function somatic mutations in the ATAD5 gene, consistent with the role of mouse Atad5 in suppressing tumorigenesis. Collectively, our findings suggest that ATAD5 may be a novel tumor suppressor gene.
- Published
- 2011