2000 Fiscal Year Annual Research Report

色素性乾皮症バリアント(XP-V)群患者におけるXPV遺伝子の変異の解析

Research Project

Project/Area Number	12771400
Research Institution	Osaka University
Principal Investigator	益谷央豪大阪大学, 細胞生体工学センター, 助手 (40241252)
Keywords	色素性乾皮症バリアント / XPV / DNAポリメラーゼη / 損傷乗り越えDNA複製
Research Abstract	高発癌性遺伝疾患である色素性乾皮症は(XP)は、A〜Gの7相補性群とバリアント(XP-V)に分類される。XP-A〜G群がヌクレオチド除去修復機構の欠損であるのに対し、XP-V群は複製後修復機構の欠損であり、他の群とは、明確に区別する必要がある。しかしながら、臨床症状の共通性が多く、臨床診断は極めて困難な現状である。申請者は、XPV責任遺伝子を同定し、その遺伝子産物がDNAポリメラーゼηであることを明らかにしてきた。本年度は、XPV遺伝子のゲノム構造を明らかにした。XPV遺伝子は、ヒトの第6番染色体上6p21.1-12に存在し、12のエキソンより構成される。蛋白質翻訳のための開始コドンは第2エキソンに含まれる。転写開始点上流には、TATA配列は存在せず、ハウスキーピング遺伝子であると考えられる。また、Sp1やE2Fなどの転写因子の結合配列が数カ所存在し、DNA複製と関連した発現制御機構の存在が示唆された。これらの成果を、遺伝子診断へ応用すべく、XPV遺伝子の各エキソンおよびその周辺をゲノムDNAよりPCRにより増幅して調べられるプライマーを設計した。4例のXP-V群患者由来細胞について検討した結果、1例では、スプライシングサイトの変異により、第2エキソンがmRNAレベルで失われること、他の3例では、エキソン内の変異を検出した。これらの変異は、いずれも蛋白質レベルでの大きな欠失をもたらすものであった。

Research Products

(17 results)

All Other

All Publications (17 results)

[Publications] Araki,M. et al.: "Reconstitution of damage DNA excision reaction from SV40 minichromosomes with purified nucleotide excision repair proteins."Mutation Research. 459. 147-160 (2000)
[Publications] Yokoi,M. et al.: "The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of TFIIH to damaged DNA."J.Biological Chemistry. 275. 9870-9875 (2000)
[Publications] Vaisman,A. et al.: "Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase η."Biochemistry. 39. 4575-4580 (2000)
[Publications] Matsuda,T. et al.: "Low fidelity DNA synthesis by human DNA polymerase η."Nature. 404. 1011-1013 (2000)
[Publications] Watanabe,Y. et al.: "Modulation of TFIIH-associated kinase activity by complex formation and its relationship with CTD phosphorylation of RNA polymerase II."Genes to Cells. 5. 407-423 (2000)
[Publications] Masutani,C. et al.: "Mechanisms of accurate translesion synthesis by human DNA polymerase η."EMBO J.. 19. 3100-3109 (2000)
[Publications] Yamada,A. et al.: "Complementation of defective translesion synthesis and ultraviolet light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase η."Nucleic Acids Research. 28. 2473-2480 (2000)
[Publications] Ohashi,E. et al.: "Error-prone bypass of certain DNA lesions by the human DNA polymerase K."Gernes and Development. 14. 1589-1594 (2000)
[Publications] Miao,F. et al.: "3-methyladenine-DNA glycosylase (MPG protein) interacts with human RAD23 proteins."J.Biological Chemistry. 275. 28433-28438 (2000)
[Publications] Yuasa,M. et al.: "Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene."Oncogene. 19. 4721-4728 (2000)
[Publications] Bebenek,K. et al.: "Proofreading of DNA polymerase η-dependent replication errors."J.Biological Chemistry. 276. 2317-2320 (2001)
[Publications] Sugasawa,K. et al.: "A multistep damage recognition mechanism for global genomic nucleotide excision repair."Genes and Development. 15. 507-521 (2001)
[Publications] Kusumoto,R. et al.: "Diversity of the damage recognition step in the global genomic nucleotide excision repair in vitro."Mutation Research. 485. 219-227 (2001)
[Publications] Ishikawa,T. et al.: "Mutagenic and non-mutagenic bypass of DNA lesions by Drosophila DNA polymerase d pol η and dpoli."J.Biological Chemistry. (in press). (2001)
[Publications] Araki,M. et al.: "Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmontosum group C complex that initiates global genome nucleotide excision repair."J.Biological Chemistry. (in press). (2001)
[Publications] Ura,K. et al.: "ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes."EMBO J.. (in press). (2001)
[Publications] Levine,R.L. et al.: "Translesion DNA synthesis catalyzed by human pol η and pol κ across I, N^6-ethenodeoxyadenosine."J.Biological Chemistry. (in press). (2001)

2000 Fiscal Year Annual Research Report

色素性乾皮症バリアント(XP-V)群患者におけるXPV遺伝子の変異の解析

Principal Investigator

益谷 央豪 大阪大学, 細胞生体工学センター, 助手 (40241252)

Research Products

[Publications] Araki,M. et al.: "Reconstitution of damage DNA excision reaction from SV40 minichromosomes with purified nucleotide excision repair proteins."Mutation Research. 459. 147-160 (2000)

[Publications] Yokoi,M. et al.: "The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of TFIIH to damaged DNA."J.Biological Chemistry. 275. 9870-9875 (2000)

[Publications] Vaisman,A. et al.: "Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase η."Biochemistry. 39. 4575-4580 (2000)

[Publications] Matsuda,T. et al.: "Low fidelity DNA synthesis by human DNA polymerase η."Nature. 404. 1011-1013 (2000)

[Publications] Watanabe,Y. et al.: "Modulation of TFIIH-associated kinase activity by complex formation and its relationship with CTD phosphorylation of RNA polymerase II."Genes to Cells. 5. 407-423 (2000)

[Publications] Masutani,C. et al.: "Mechanisms of accurate translesion synthesis by human DNA polymerase η."EMBO J.. 19. 3100-3109 (2000)

[Publications] Yamada,A. et al.: "Complementation of defective translesion synthesis and ultraviolet light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase η."Nucleic Acids Research. 28. 2473-2480 (2000)

[Publications] Ohashi,E. et al.: "Error-prone bypass of certain DNA lesions by the human DNA polymerase K."Gernes and Development. 14. 1589-1594 (2000)

[Publications] Miao,F. et al.: "3-methyladenine-DNA glycosylase (MPG protein) interacts with human RAD23 proteins."J.Biological Chemistry. 275. 28433-28438 (2000)

[Publications] Yuasa,M. et al.: "Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene."Oncogene. 19. 4721-4728 (2000)

[Publications] Bebenek,K. et al.: "Proofreading of DNA polymerase η-dependent replication errors."J.Biological Chemistry. 276. 2317-2320 (2001)

[Publications] Sugasawa,K. et al.: "A multistep damage recognition mechanism for global genomic nucleotide excision repair."Genes and Development. 15. 507-521 (2001)

[Publications] Kusumoto,R. et al.: "Diversity of the damage recognition step in the global genomic nucleotide excision repair in vitro."Mutation Research. 485. 219-227 (2001)

[Publications] Ishikawa,T. et al.: "Mutagenic and non-mutagenic bypass of DNA lesions by Drosophila DNA polymerase d pol η and dpoli."J.Biological Chemistry. (in press). (2001)

[Publications] Araki,M. et al.: "Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmontosum group C complex that initiates global genome nucleotide excision repair."J.Biological Chemistry. (in press). (2001)

[Publications] Ura,K. et al.: "ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes."EMBO J.. (in press). (2001)

[Publications] Levine,R.L. et al.: "Translesion DNA synthesis catalyzed by human pol η and pol κ across I, N^6-ethenodeoxyadenosine."J.Biological Chemistry. (in press). (2001)

益谷央豪大阪大学, 細胞生体工学センター, 助手 (40241252)