Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia

• Project/Area Number: 24790321
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Nagasaki University
• Principal Investigator: NAKAZAWA Yuka 長崎大学, 原爆後障害医療研究所, 助教 (00533902)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: DNA修復 / ヌクレオチド除去修復 / 分子遺伝子診断学 / DNA損傷修復

Outline of Final Research Achievements

Nucleotide excision repair (NER) removes sunlight-induced photolesions from DNA. There are several NER-deficient human disorders: Cockayne syndrome (CS) is characterised by developmental abnormalities as well as sun-sensitivity, while xeroderma pigmentosum (XP) is associated with skin cancer predisposition. UV-sensitive syndrome (UVSS) patients only display mild skin photosensitivity.
We have previously identified 12 CS-patients who did not have mutations in any of known CS-genes. In this research, we further analysed the CS-cases and characterise three CS patients deficient in ERCC1 or ERCC4 (XPF) genes. Interestingly, one of these patients with mutations in XPF had clinical features of CS, XP, and Fanconi anemia (FA). Our results indicate a multifunctional role for the ERCC1-XPF endonuclease.

Research Products

• [Journal Article] A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents. (2015)
  • Author(s): Nan Jia, Yuka Nakazawa, Chaowan Guo, Mayuko Shimada, Mieran Sethi, Yoshito Takahashi, Hiroshi Ueda, Yuji Nagayama, Tomoo Ogi
  • Journal Title: Nature Protocols Volume: 10 Issue: 1 Pages: 12-24
  • DOI: 10.1038/nprot.2014.194
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypomorphic PCNA mutation underlies a human DNA repair disorder. (2014)
  • Author(s): Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, Crosby AH.
  • Journal Title: Journal of Clinical Investigation Volume: 124 Issue: 7 Pages: 3137-3146
  • DOI: 10.1172/jci74593
  • Peer Reviewed
• [Journal Article] Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia. (2013)
  • Author(s): Kashiyama, K, Nakazawa, Y, Pilz, DT, Guo, C, Sasaki, K, et al.
  • Journal Title: The American Journal of Human Genetics Volume: 92 Issue: 5 Pages: 807-819
  • DOI: 10.1016/j.ajhg.2013.04.007
  • Peer Reviewed
• [Journal Article] Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome (2012)
  • Author(s): *Ogi T , Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, Prescott K, Suri M, Byrd P, Matsuse M, Mitsutake N, Nakazawa Y, Vasudevan P, Barrow M, Stewart G, Taylor M, O'Driscoll M, and Jeggo P
  • Journal Title: PLoS Genetics Volume: 8 Issue: 11 Pages: e1002945-e1002945
  • DOI: 10.1371/journal.pgen.1002945
  • NAID: 120006985789
  • Peer Reviewed
• [Journal Article] Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair (2012)
  • Author(s): Nakazawa Y, Sasaki K, Mitsutake N, Yamashita S, Ogi T, et al
  • Journal Title: Nat Genet Volume: 44(5) Issue: 5 Pages: 586-92
  • DOI: 10.1038/ng.2229
  • NAID: 120006985586
  • Peer Reviewed
• [Presentation] 放射線感受性および各種発達異常を示す遺伝性疾患の新規責任遺伝子の同定と分子機能解析 (2014)
  • Author(s): 中沢由華、郭朝万、嶋田繭子、宮崎仁美、唐田清伸、荻朋男
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Molecular and functional study on the initiation of transcription coupled nucleo tide excision repair (2014)
  • Author(s): Guo C, Nakazawa Y, Shimada M, Jia N, Karata K, Miyazaki H, Ogi T.
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] コケイン症候群様の臨床症状を示す遺伝性疾患の責任遺伝子探索 (2014)
  • Author(s): 宮崎仁美、中沢由華、郭朝万、嶋田繭子、賈楠、唐田清伸、荻朋男
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] エキソーム解析を用いたDNA修復機構欠損性疾患の新規責任遺伝子の探索 (2014)
  • Author(s): 嶋田繭子、中沢由華、郭朝万、賈楠、宮崎仁美、唐田清伸、荻朋男
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] ERCC1/XPF deficiency causes three NER- deficient disorders: a patient with various symptoms of xeroderma pigmentosum, Cockayne syndrome & Fanconi anemia. (2014)
  • Author(s): Nakazawa Y, Kashiyama K, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H, Wing JF, Lewin SO, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Mitsutake N, Lehmann AR, Ogi T.
  • Organizer: The 9th 3R Symposium
  • Place of Presentation: 御殿場高原ホテル（静岡県御殿場市）
  • Year and Date: 2014-11-17 – 2014-11-21
• [Presentation] Molecular characterization and functional analysis of XRCC4, a novel pathological gene for radiation sensitivity and developmental abnormalities (2014)
  • Author(s): Guo C, Nakazawa Y, Shimada M, Woodbine L, Jia N, Karata K, Miyazaki H, Lehmann A, Jeggo PA, Ogi T.
  • Organizer: The 9th 3R Symposium
  • Place of Presentation: 御殿場高原ホテル（静岡県御殿場市）
  • Year and Date: 2014-11-17 – 2014-11-21
• [Presentation] Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia (2013)
  • Author(s): 中沢由華
  • Organizer: 11th International Conference on Environmental Mutagens
  • Place of Presentation: Bourbon Convention & Spa Resort Cataratas do Iguassu（ブラジル）
• [Presentation] RNA polymerase processing in nucleotide-excision-repair-deficient genetic disorders
  • Author(s): 中沢 由華
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡市
• [Remarks] 長崎大学 がん・ゲノム不安定性研究拠点ホームページ
  • URL: http://www.nrgic.prj.nagasaki-u.ac.jp/
• [Remarks] 長崎大学 がん・ゲノム不安定性研究拠点ホームページ
  • URL: http://www.nrgic.prj.nagasaki-u.ac.jp/