title: Predisposition to cancer caused by genetic and functional defects of mammalian Atad5.
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.
authors: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America. belldaph@mail.nih.gov
authors: Daphne W
authors: DW
authors: Bell
authors: Nilabja
authors: N
authors: Sikdar
authors: Kyoo-Young
authors: KY
authors: Lee
authors: Jessica C
authors: JC
authors: Price
authors: Raghunath
authors: R
authors: Chatterjee
authors: Hee-Dong
authors: HD
authors: Park
authors: Jennifer
authors: J
authors: Fox
authors: Masamichi
authors: M
authors: Ishiai
authors: Meghan L
authors: ML
authors: Rudd
authors: Lana M
authors: LM
authors: Pollock
authors: Sarah K
authors: SK
authors: Fogoros
authors: Hassan
authors: H
authors: Mohamed
authors: Christin L
authors: CL
authors: Hanigan
authors: Suiyuan
authors: S
authors: Zhang
authors: Pedro
authors: P
authors: Cruz
authors: Gabriel
authors: G
authors: Renaud
authors: Nancy F
authors: NF
authors: Hansen
authors: Praveen F
authors: PF
authors: Cherukuri
authors: Bhavesh
authors: B
authors: Borate
authors: Kirk J
authors: KJ
authors: McManus
authors: Jan
authors: J
authors: Stoepel
authors: Payal
authors: P
authors: Sipahimalani
authors: Andrew K
authors: AK
authors: Godwin
authors: Dennis C
authors: DC
authors: Sgroi
authors: Maria J
authors: MJ
authors: Merino
authors: Gene
authors: G
authors: Elliot
authors: Abdel
authors: A
authors: Elkahloun
authors: Charles
authors: C
authors: Vinson
authors: Minoru
authors: M
authors: Takata
authors: James C
authors: JC
authors: Mullikin
authors: Tyra G
authors: TG
authors: Wolfsberg
authors: Philip
authors: P
authors: Hieter
authors: Dae-Sik
authors: DS
authors: Lim
authors: Kyungjae
authors: K
authors: Myung
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C546328:ATAD5 protein, human; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities