Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

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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.
Publisher
PUBLIC LIBRARY SCIENCE
Issue Date
2011-08
Language
English
Article Type
Article
Keywords

REPLICATION-FACTOR-C; COMPARATIVE GENOMIC HYBRIDIZATION; GROSS CHROMOSOMAL REARRANGEMENTS; DNA-POLYMERASE-ETA; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; ENDOMETRIAL CARCINOMA; XERODERMA-PIGMENTOSUM; CELL-LINE; INSTABILITY

Citation

PLOS GENETICS, v.7, no.8

ISSN
1553-7390
URI
http://hdl.handle.net/10203/97437
Appears in Collection
BS-Journal Papers(저널논문)
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