Effects of Ionizing Radiation on Chromosome Replication and its Modification by HDAC Inhibitors

Abstract

Ionizing radiation causes lethal injuries either directly or indirectly inducing damage to the biological macromolecules, most importantly the genetic material or DNA. Cells transiently halt their cell cycle progression to provide sufficient time for repair machinery to act on for the repair of radiation-induced DNA damages. This may include delay in replication or S-phase of cell cycle besides activating other cell cycle checkpoints. Multiple replicons (replicon cluster equivalent to a chromosome band) along the length of a chromosome fire in a definite pattern for the timely completion of replication. Histone deacetylase inhibitors (HDACi) have been shown to alter the pattern of DNA replication origin activity including earlier replication in S-phase of normally late replicating chromosome bands. This may also indicate an acceleration of repair steps since DNA damage acts as an impediment for replication. Trichostatin A (TSA), a well-known HDACi, was studied for its effect on replication initiation using Indian Muntjac cell as a model. It was found that TSA treatment enhanced the replication rate and increased the number of replicon clusters firing at any given time per chromosome. It also compensated the decline of replication rate in irradiated cells, helped in their revival and brought them to the control level.