Wilhelm bernhard workshop on the cell nucleus

Polymorphism of nuclear multi-functional protein XPD and its influence on DNA repair

Rzeszowska-Wolny J.¹, Pietrowska M.¹, Polanska J.³, Palyvoda O.¹, Jaworska J.¹, Butkiewicz D.², Hancock R⁴.

¹Department of Experimental and Clinical Radiobiology; ²Department of Tumor Biology, M. Sklodowska-Curie Memorial Institute, Centre of Oncology, and ³Institute of Automation, Technical University, Gliwice, Poland; ⁴Laval University Cancer Research Centre, Quebec, Canada
The protein XPD, a 5’-3’ helicase and a component of the basal transcription factor TFIIH, is also involved in DNA repair. Repair mechanisms maintain genomic stability by detecting and correcting damaged DNA sequences and by signaling cell death when DNA repair fails. All living cells contain repair mechanisms specialized in recognition and removal of different types of DNA damage; oxidative damage is generally removed by base excision repair (BER), bulky DNA adducts by nucleotide excision repair (NER), mismatched bases by mismatch repair, and strand breaks by non-homologous end joining or homologous recombination. XPD takes part in the NER pathway. The repair pathways and their proteins are conserved in different species; however recently it was shown that polymorphic variants of some genes coding for repair proteins are present in human populations and can influence repair capacity and cancer risk of carriers. In this report we show that polymorphism of the XPD protein can cause the engagement of NER in removal of radiation-induced oxidative damage from DNA. Individuals differ in their reaction to the same dose of genotoxic agents and cultured cells from different donors show differences in DNA repair kinetics and efficiency. In studies performed in vitro on lymphocytes of 80 individuals, we assessed DNA damage and repair induced by gamma-irradiation. Cells homozygous for the XPD allele containing Asn in codon 312 showed significantly more efficient repair of radiation-induced DNA damage than homozygotes with Asp in this position. Our results suggest that NER takes part in repair of ionizing radiation-induced DNA damage and also that polymorphism in genes coding for proteins of this pathway can influence an individual’s response to ionizing radiation.

Supported by State Committee for Scientific Research (KBN, Poland) Grant 4 P05A 015 19 and Canadian Institutes of Health Research grant MOP-14351