Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-deficient mice.
Retroviral insertional mutagenesis preferentially identifies oncogenes rather than tumor suppressor (TS) genes, presumably because a single retroviral-induced mutation is sufficient to activate an oncogene and initiate a tumor, whereas two mutations are needed to inactivate a TS gene. Here we show that TS genes can be identified by insertional mutagenesis when the screens are performed in Blm-deficient backgrounds. Blm-deficient mice, like Bloom syndrome patients, have increased frequencies of mitotic recombination owing to a mutation in the RecQ protein-like-3 helicase gene. This increased mitotic recombination increases the likelihood that an insertional mutation in one allele of a TS gene will become homozygoused by non-sister chromatid exchange and the homozygosity of the insertion provides a marker for identifying the TS gene. We also show that known as well as novel TS genes can be identified by insertional mutagenesis in Blm-deficient mice and identify two JmjC family proteins that contribute to genome stability in species as evolutionarily diverse as mammals and Caenorhabditis elegans.
Suzuki
Takeshi
T
Cancer Genetic Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto, Japan. suzukit@hmro.med.kyoto-u.ac.jp
Minehata
Ken-ichi
K
Akagi
Keiko
K
Jenkins
Nancy A
NA
Copeland
Neal G
NG
D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001816:Bloom Syndrome / Q000235:genetics; D003433:Crosses, Genetic; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D005820:Genetic Testing; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D053484:RecQ Helicases; D012190:Retroviridae / Q000235:genetics*; D016662:Virus Integration / Q000235:genetics
D014408:Biomarkers, Tumor; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases