Predisposition to cancer caused by genetic and functional defects of mammalian atad5

Daphne W. Bell, Nilabja Sikdar, Kyoo Young Lee, Jessica C. Price, Raghunath Chatterjee, Hee Dong Park, Jennifer Fox, Masamichi Ishiai, Meghan L. Rudd, Lana M. Pollock, Sarah K. Fogoros, Hassan Mohamed, Christin L. Hanigan, Comparative Sequencing Program NISC Comparative Sequencing Program, Suiyuan Zhang, Pedro Cruz, Gabriel Renaud, Nancy F. Hansen, Praveen F. Cherukuri, Bhavesh BorateKirk J. McManus, Jan Stoepel, Payal Sipahimalani, Andrew K. Godwin, Dennis C. Sgroi, Maria J. Merino, Gene Elliot, Abdel Elkahloun, Charles Vinson, Minoru Takata, James C. Mullikin, Tyra G. Wolfsberg, Philip Hieter, Dae Sik Lim, Kyungjae Myung

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1002245
JournalPLoS genetics
Volume7
Issue number8
DOIs
StatePublished - Aug 1 2011

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Bell, D. W., Sikdar, N., Lee, K. Y., Price, J. C., Chatterjee, R., Park, H. D., Fox, J., Ishiai, M., Rudd, M. L., Pollock, L. M., Fogoros, S. K., Mohamed, H., Hanigan, C. L., NISC Comparative Sequencing Program, C. S. P., Zhang, S., Cruz, P., Renaud, G., Hansen, N. F., Cherukuri, P. F., ... Myung, K. (2011). Predisposition to cancer caused by genetic and functional defects of mammalian atad5. PLoS genetics, 7(8), [e1002245]. https://doi.org/10.1371/journal.pgen.1002245