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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.

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