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Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian <i>Atad5</i>
Bell, Daphne W.,Sikdar, Nilabja,Lee, Kyoo-young,Price, Jessica C.,Chatterjee, Raghunath,Park, Hee-Dong,Fox, Jennifer,Ishiai, Masamichi,Rudd, Meghan L.,Pollock, Lana M.,Fogoros, Sarah K.,Mohamed, Hassa Public Library of Science 2011 PLoS genetics Vol.7 No.8
<▼1><P>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 <I>in vivo</I>. To test this hypothesis, we generated heterozygous (<I>Atad5<SUP>+/m</SUP></I>) mice that were haploinsuffficient for Atad5. <I>Atad5<SUP>+/m</SUP></I> mice displayed high levels of genomic instability <I>in vivo</I>, and <I>Atad5<SUP>+/m</SUP></I> 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 <I>Atad5<SUP>+/m</SUP></I> 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 <I>Atad5<SUP>+/m</SUP></I> mice. Consistent with a role for <I>Atad5</I> in suppressing tumorigenesis, we also identified somatic mutations of <I>ATAD5</I> 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 <I>Atad5</I> are sufficient to cause genomic instability and tumorigenesis.</P></▼1><▼2><P><B>Author Summary</B></P><P>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 <I>Atad5</I> 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 <I>ATAD5</I> gene, consistent with the role of mouse <I>Atad5</I> in suppressing tumorigenesis. Collectively, our findings suggest that <I>ATAD5</I> may be a novel tumor suppressor gene.</P></▼2>