1995 Fiscal Year Final Research Report Summary
Analysis of DNA repair functions of xeroderma pigmentosum gene
| Project/Area Number |
06404077
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Human genetics
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| Research Institution | Osaka University |
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Principal Investigator |
TANAKA Kiyoji Institute for Molecular and Cellular Biology, Osaka University, Division of Cellular Genetics, Professor, 細胞生体工学センター, 教授 (80144450)
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| Co-Investigator(Kenkyū-buntansha) |
SAIJO Masafumi Institute for Molecular and Cellular Biology, Osaka University, Division of Cell, 細胞生体工学センター, 助手 (90221986)
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| Project Period (FY) |
1994 – 1995
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| Keywords | DNA repair / xeroderma pigmentosum / DNA binding / Zn-finger / gene targeting / knock-out mouse / carcinogenesis / p53 gene |
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| Research Abstract |
XPA gene is a causative gene for human genetic disease, xeroderma pigmentosum group A (XPA) and one of the important genes responsible for nucleotide excision repair (NER) in man and encodes a protein of 273 amino acids. We found that the XPA gene product (XPA protein) preferentially bound to the damaged DNA,suggesting its role in damage recognition step of NER.The damaged DNA binding activity is localized in the region encompassed by the MF122 protein (amino acid residues 98 to 219) which is a discretely folded, functional mini-domain, and contains C4 zinc-finger motif. Moreover, the XPA protein has domains to interact with other proteins. Using yeast two hybrid system, we found that the ERCC1 repair protein, replication protein A (RPA) and several other proteins bind to the XPA protein.
The interaction between XPA and ERCC1 or RPA enhanced the damaged DNA binding activity of the XPA protein, suggesting that the interaction may coordinate the damage-recognition step of NER.Yeast homologs of new XPA-binding proteins have been cloned. We are making yeast mutants lacking these genes to see whether they will show a defective NER.
We established XPA-deficient mice using gene targeting technology in ES cells. They are defective in NER and highly susceptible to ultraviolet light-or chemical carcinogen-induced skin carcinogeneis. They also had smaller brain. The XPA-deficient mice may provide a useful tool to study a multistep process of ultraviolet light-induced skin carcinogenesis and a molecular basis of the neurological disturbance in xeroderma pigmentosum patients.
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Research Products
(12 results)
