Werner and Bloom helicases are involved in DNA repair in a complementary fashion.
Werner syndrome (WS) is a recessive disorder characterized by premature senescence. Bloom syndrome (BS) is a recessive disorder characterized by short stature and immunodeficiency. A common characteristic of both syndromes is genomic instability leading to tumorigenesis. WRN and BLM genes causing WS and BS, encode proteins that are closely related to the RecQ helicase. We produced WRN-/-, BLM-/- and WRN(-/-)/BLM(-/-) mutants in the chicken B-cell line DT40. WRN-/- cells showed hypersensitivities to genotoxic agents, such as 4-nitroquinoline 1-oxide, camptothecin and methyl methanesulfonate. They also showed a threefold increase in targeted integration rate of exogenous DNAs, but not in sister chromatid exchange (SCE) frequency. BLM-/- cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency. In WRN(-/-)/BLM(-/-) cells, synergistically increased hypersensitivities to the genotoxic agents were observed whereas both SCE frequencies and targeted integration rates were partially diminished compared to the single mutants. Chromosomal aberrations were also synergistically increased in WRN(-/-)/BLM(-/-) cells when irradiated with UV light in late S to G(2) phases. These results suggest that both WRN and BLM may be involved in DNA repair in a complementary fashion.
Imamura
Osamu
O
AGENE Research Institute, 200 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
Fujita
Kumiko
K
Itoh
Chie
C
Takeda
Shunichi
S
Furuichi
Yasuhiro
Y
Matsumoto
Takehisa
T
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D001816:Bloom Syndrome / Q000201:enzymology / Q000235:genetics; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D002645:Chickens; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D018390:Gene Targeting; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests; D011836:Radiation Tolerance; D053484:RecQ Helicases; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013045:Species Specificity; D014466:Ultraviolet Rays; D014898:Werner Syndrome / Q000201:enzymology / Q000235:genetics
D015112:4-Nitroquinoline-1-oxide; D005047:Etoposide; D004247:DNA; D008741:Methyl Methanesulfonate; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; C506731:RECQL4 protein, human; D004265:DNA Helicases; D053484:RecQ Helicases; D002166:Camptothecin