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発表内容

Title:
Molecular cloning and characterisation of human DNA repair genes

Tomoo Ogi
Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (NRGIC), Nagasaki, Japan, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
togi@nagasaki-u.ac.jp

Abstract:
Cells are continuously exposed to many types of DNA damaging activities, including ionising radiation (IR), sunlight ultraviolet (UV), environmental pollutants, and various metabolic actions. Consequently, all living organisms have developed efficient DNA repair mechanisms to warrant that the integrity of genetic information is stably maintained. Our research is focused on the molecular mechanisms of human DNA damage response (DDR) systems, especially in the DNA damage checkpoint and the damage repair pathways of UV-induced photolesions. Nucleotide excision repair (NER), is the most versatile DNA repair system, which removes the major UV-photolesions as well as bulky base adducts from cellular DNA. In mammals, compromised NER activity is the cause of several cancer predisposition diseases including xeroderma pigmentosum (XP). We have established a rapid and efficient screening system for measuring NER related DNA repair activities; based on the system, we are running diagnostic services for DDR-deficiency related genetic disorders. Last three years of our activities, we totally diagnosed ~300 patients who displayed DDR-compromised clinical manifestations. We extracted DDR-deficient patients whose genetic causes have yet to be identified. These cases were further analysed their genomes to determine the disease causative mutations by next generation DNA sequencing platforms. From the cellular and the genetic combinatorial screenings, we have identified 6 new pathogenic DDR genes: UVSSA from two unrelated Japanese UV-sensitive syndrome cases; ATRIP from a Seckel syndrome family; PRKDC from a SCID patient; ERCC1 and XPF from Cockayne syndrome patients. Detailed molecular pathogenesis for the DDR diseases have been studied.

References:
Kashiyama et al., Malfunction of the ERCC1/XPF endonuclease results in diverse clinical manifestations and causes three nucleotide excision-repair-deficient disorders, Cockayne Syndrome, xeroderma pigmentosum and Fanconi Anemia.
American Journal of Human Genetics 92: 807-819 (2013)

Ogi et al., Identification of the First ATRIP-Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR-ATRIP Seckel Syndrome.
PLoS Genetics 8: e1002945 (2012)

Nakazawa et al., Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
Nature Genetics 44: 586-592 (2012)