HIGHER-ORDER CHROMATIN STRUCTURE-DEPENDENT REPAIR OF DNA DOUBLE-STRAND BREAKS - MODELING THE ELUTION OF DNA FROM NUCLEOIDS

A possible relationship between the repair of DNA double-strand breaks (DSBs) and their distribution within higher-order chromatin (Johnston and Bryant, Int. J. Radiat. Biol. 66, 531-536, 1994) has recently bee n demonstrated. Radiosensitive cells deficient for components of the D NA-dependent protein kinase DSB repair pathway exhibited a particular failure in the rejoining of DSBs occurring as multiples within looped DNA structures. Here, a Poisson-based model of induction of DSBs and e lution of DNA from residual nuclear structures is presented. By applyi ng this model to cells of a panel of human and rodent cell lines, a me an of 1.6 Mbp for the size of the relevant looped structures was obtai ned. Such large chromatin structures are of the same magnitude as thos e observed by functional mapping of interphase and mitotic chromosome structure, nucleoid sedimentation and the ''replicon clusters'' appare nt during DNA replication. This work supports the hypotheses that (1) such structures are critical targets for induction of DSBs and (2) the distribution of damage within these domains may be a factor in the re sponse and sensitivity of mammalian cells to ionizing radiation. (C) 1 997 by Radiation Research Society.