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 been demonstrated. Radiosensitive cells deficient for components of the DNA-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 elution of DNA from residual nuclear structures is presented. By applying this model to cells of a panel of human and rodent cell lines, a mean of 1.6 Mbp for the size of the relevant looped structures was obtained. Such large chromatin structures are of the same magnitude as those observed by functional mapping of interphase and mitotic chromosome structure, nucleoid sedimentation and the "replicon clusters" apparent 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 response and sensitivity of mammalian cells to ionizing radiation.