Modeling Cell Survival after Photon Irradiation Based on Double-Strand Break Clustering in Megabase Pair Chromatin Loops

Abstract

A new, simple mechanistic dose-response model for cell survival after photon irradiation is presented. Its ingredients are motivated by the concept of giant loops, which constitute a level of chromatin organization on a megabase pair length scale. Double-strand breaks (DSBs) that are induced within different loop domains of the DNA are assumed to be processed independently by the cell's repair mechanism. The model distinguishes between two classes of damage, characterized by either a single DSB or multiple DSBs within a single loop. Different repair fidelities are associated with these two damage classes from which lethality of damages and consequently the survival probability of cells is derived. Given the giant loop chromatin organization and the assumption of two damage classes represent the main pillars of this new approach, we propose to call it the Giant LOop Binary LEsion (GLOBLE) approach. In this paper, we discuss the motivation and the formulation of the model as well as some basic implications. First applications to experimental data obtained with 250 kV X-rays exhibit that the model is able to reveal important features of the dose-response curves describing cell survival. These comprise a linear-quadratic behavior at lower doses and a transition to a straight dose-response relationship at high doses. We establish relationships to the parameters α and β of the linear-quadratic model and discuss possible generalizations. When expressed in terms of the linear-quadratic model, we demonstrate that our new model predicts an intrinsic anticorrelation between β and α, in line with an analysis of a large set of experimental data that is based on survival curves for more than 150 cell lines.