title: Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis.
abstract: Damage-specific DNA-binding (DDB) protein heterodimer has been extensively studied in the context of nucleotide excision repair. However, the smaller subunit, DDB2, is also implicated in tumor suppressor p53-mediated processes, although the precise details of the DDB2 - p53 interactions are unknown. Here, we report that Ddb2(-/-) and Ddb2(+/-) mice have shortened lifespans and increased frequency and spectrum of spontaneous tumors. Notably, Ddb2 deficiency enhances lung and mammary adenocarcinomas. Ddb2(-/-) mice are smaller than normal. Whereas weights of kidneys and livers are reduced proportionately, spleens from Ddb2(-/-) mice gradually enlarge with age due to lymphoid proliferation. Ddb2(-/-) mice also have larger testes, and the testicular germ cells show significantly decreased spontaneous apoptosis. These changes parallel reduced levels of p53 and its serine 15 phosphorylation in testicular germ cells. Since tumors that appeared in heterozygous Ddb2(+/-) mice conserve the wild-type Ddb2 allele, Ddb2 RNA expression and Ddb2 exon sequence, Ddb2 heterozygosity can facilitate tumor development as a haploinsufficient tumor suppressor. These results demonstrate that in whole animals as in cultured cells Ddb2 can regulate apoptosis and tumor incidence.
authors.affiliation: Department of Pathology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. toshiki-ito@uiowa.edu
authors.forename: Toshiki
authors.initials: T
authors.lastname: Itoh
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Iwashita
authors.forename: Michael B
authors.initials: MB
authors.lastname: Cohen
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Stuart
authors.initials: S
authors.lastname: Linn
mesh_terms: D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology*; D018572:Disease-Free Survival; D016158:Genes, p53; D005854:Germ Cells / Q000166:cytology* / Q000473:pathology; D006579:Heterozygote; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D012694:Serine / Q000737:chemistry; D013154:Spleen / Q000378:metabolism; D013737:Testis / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D012694:Serine