title: Radiation induced base excision repair (BER): a mechanistic mathematical approach.
abstract: This paper presents a mechanistic model of base excision repair (BER) pathway for the repair of single-stand breaks (SSBs) and oxidized base lesions produced by ionizing radiation (IR). The model is based on law of mass action kinetics to translate the biochemical processes involved, step-by-step, in the BER pathway to translate into mathematical equations. The BER is divided into two subpathways, short-patch repair (SPR) and long-patch repair (LPR). SPR involves in replacement of single nucleotide via Pol β and ligation of the ends via XRCC1 and Ligase III, while LPR involves in replacement of multiple nucleotides via PCNA, Pol δ/ɛ and FEN 1, and ligation via Ligase I. A hallmark of IR is the production of closely spaced lesions within a turn of DNA helix (named complex lesions), which have been attributed to a slower repair process. The model presented considers fast and slow component of BER kinetics by assigning SPR for simple lesions and LPR for complex lesions. In the absence of in vivo reaction rate constants for the BER proteins, we have deduced a set of rate constants based on different published experimental measurements including accumulation kinetics obtained from UVA irradiation, overall SSB repair kinetic experiments, and overall BER kinetics from live-cell imaging experiments. The model was further used to calculate the repair kinetics of complex base lesions via the LPR subpathway and compared to foci kinetic experiments for cells irradiated with γ rays, Si, and Fe ions. The model calculation show good agreement with experimental measurements for both overall repair and repair of complex lesions. Furthermore, using the model we explored different mechanisms responsible for inhibition of repair when higher LET and HZE particles are used and concluded that increasing the damage complexity can inhibit initiation of LPR after the AP site removal step in BER.
authors.affiliation: Radiation Biophysics Group, Department of Oncology-Pathology, Karolinska Institutet, Box 260 P9-02, Stockholm 17176, Sweden.
authors.forename: Shirin
authors.initials: S
authors.lastname: Rahmanian
authors.affiliation: Radiation Physics, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 94, Houston, TX 77030-4409, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Taleei
authors.affiliation: Radiation Biophysics Group, Department of Oncology-Pathology, Karolinska Institutet, Box 260 P9-02, Stockholm 17176, Sweden. Electronic address: hooshang.nikjoo@ki.se.
authors.forename: Hooshang
authors.initials: H
authors.lastname: Nikjoo
mesh_terms: D000818:Animals; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D006801:Humans; D008957:Models, Genetic; D014466:Ultraviolet Rays
keywords: BER; Damage complexity; Mathematical model; Mechanistic model; Repair kinetics; SSB