2010;285:22630C22638
2010;285:22630C22638. detect differential expression of DNA repair genes in the cerebellum revealed perturbation of p53 signaling in mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between and by suggesting that p53/p21-mediated apoptosis and/or senescence may be involved Rabbit polyclonal to AMACR in synthetic lethal interactions occurring during development and inhibition of tumor growth. null animals toward the mutagenic effect of DNA damaging agents [8]. The gene encodes a dsDNA-dependent ATPase of the Swi2/Snf2 family [9], which interacts directly with Rad51 [10,11], and stimulates its DNA exchange activity [12]. Rad54 promotes chromatin remodeling, Rad51 displacement from double-stranded DNA, binds Holliday junctions and drives their branch migration [13]. Although disruption of other genes involved in HR leads Metixene hydrochloride to embryonic lethality, adult gene family have been found in primary tumors (and in development and oncogenesis and inactivating mutations in a well characterized cancer model, the heterozygous mice. Mice in which one copy the gene has been inactivated (and or of and increased radiation induced MB [21,22]. Here, we analyzed the effects of combined loss of and in the Metixene hydrochloride mouse model of spontaneous and radiation-induced cancer, highlighting novel synthetic lethal interactions during development and tumorigenesis, and dissecting the underlying cellular and molecular mechanisms. RESULTS Survival and oncogenesis in crosses between and mutant mice Defects in DNA damage signaling are frequently associated with neurodegeneration, neurodevelopmental disease and brain tumors. We therefore sought to determine the oncogenic potential of combined genetic disruption of and in the CNS by knocking out these genes in genotypes are hereafter omitted from the label, unless differently specified. Mutants for ((genotype, no mice with compound inactivation were found at Metixene hydrochloride weaning, showing strong synthetic lethal interaction between and genes data. To look for haploinsufficient interactions, compound mutant mice with varying gene dosage of and were analyzed for survival and cerebellum tumorigenesis, with or without irradiation. Because only and inactivation was evaluated only in mice with affected lifespan of ? 0.0001) or 45 weeks (= 0.0206), respectively (Figure ?(Figure1A1A and ?and1C).1C). However, loss of function had more severe effects on survival compared to loss (i.e., 14 45 weeks; = 0.0002) (Figure ?(Figure1A),1A), suggesting a preferential role for in resolution of spontaneous DNA damage compared to compound mutants (64 weeks ? 0.0001; 13 45 weeks; = 0.0002; Figure 1A-1C), with median survival reduced approximately 3-fold. Notably, life shortening was not affected by status, in agreement with findings that compound mutants (= 0.862; Figure 1A-1C). The lack of modifying effects of on and inactivation on survival and tumor development(A) Survival curves of unirradiated null mice (and inactivation on spontaneous and (E) radiation-induced medulloblastoma tumorigenesis. (F) Percent incidence of medulloblastoma, sarcoma and other tumors for each mouse group. * 0.05; ** 0.005; *** 0.0001. Coherent with survival reduction, genetic disruption of significantly increased spontaneous MB incidence in 14% in = 0.0038) or in (the viable genotypes: 15%, respectively; = 0.0274) (Figure 1D-1F). Irradiation of background [= 0.0001); = 0.0001)] and in heterozygotes (= 0.0447) (Figure 1D-1F). In contrast, irradiation of = 0.1717). This difference became significant only in mice with concurrent inactivation of one copy of [(= 0.0378)] (Figure ?(Figure1E1E and ?and1F).1F). Notably, in a null background deletion of one allele caused significantly lower radiation-induced MB tumorigenesis compared with mice [= 0.0439] (Figure ?(Figure1E1E and ?and1F),1F), suggesting a lethal haploinsufficient interaction between and in the context of radiation oncogenesis. In all groups, irradiation increased the incidence of MB, an early-onset tumor. This was reflected in decreased incidence of late occurring tumors, including sarcomas and other tumors (Figure ?(Figure1F),1F), with exception of allele is the causative event in MB development Metixene hydrochloride in and deficiency alters the typical chr-13 LOH pattern in MB, we performed microsatellite analysis with a set Metixene hydrochloride of markers spanning the length of chr-13, where gene is located (Figure S1). Within the.