CONSTANCY OF THE RELATIVE BIOLOGICAL EFFECTIVENESS OF 42 MEV (P-]BE-LINES WITH DIFFERENT DNA-REPAIR PROFICIENCIES() NEUTRONS AMONG CELL)

An important approach to understanding the role of the various DNA rep air pathways in the cellular response to DNA-damaging agents is throug h the study of repair-deficient mutant cell lines, In the present stud y we used this strategy to assess the relative importance of four of t hese pathways for the repair of DNA damage induced by low-linear energ y transfer (LET) gamma rays and intermediate-LET 42 MeV (p-->Be+) fast neutrons. The panel of hamster cell mutants that we characterized for their relative sensitivity to fast neutrons and gamma rays includes c ell lines with defects in the nucleotide excision repair pathway; thes e can be further subdivided into mutants which are defective in nucleo tide excision repair alone [UV5 (ERCC2(-)), UV24 (ERCC3(-)), UV135 (ER CC5(-)) and UV61 (ERCC6(-))] compared to those which have an associate d defect in the distinct but overlapping pathway for the repair of DNA crosslinks [UV20 (ERCC1(-)) and UV41 (ERCC4(-))]. We also examined mu tants with defects in the base excision repair pathway [EM9 (XRCC1(-)) ] and the DNA-dependent protein kinase (DNA-PK)-mediated DNA double-st rand break (DSB) repair pathway [xrs5 (XRCC5(-))]. None of the mutants defective in nucleotide excision repair was differentially sensitized to fast neutrons or gamma rays; in fact, the slight radiosensitivity of these mutants under aerated conditions may be secondary to their de fect in nucleotide excision repair, In contrast, deficiency in the bas e excision repair pathway resulted in a significant primary sensitizat ion to both types of radiation (1.95-fold to gamma rays and 1.79-fold to neutrons). Deficiency in the DSB repair pathway mediated by DNA-PK resulted in a marked, but again similar, primary sensitization to gamm a rays (4.2-fold) and neutrons (5.1-fold), Thus none of the repair pat hways examined here exhibited a preferential role for the repair of da mage induced by low-LET compared to intermediate-LET radiations; this resulted in an essentially constant relative biological effectiveness (RBE) of similar to 2 among the cell lines studied, independent of the ir DNA repair proficiency, However, consideration of these data along with data published previously for high-LET alpha particles suggests t hat, whereas the DNA-PK pathway is important for the repair of DSBs in duced by low- and intermediate-LET radiations, it becomes less importa nt as the LET increases beyond 100 keV/mu m; thus this pathway may not be involved in repairing the more complex lesions induced by densely ionizing high-LET particles. (C) 1997 by Radiation Research Society.