Base Excision Repair in Chromatin and the Requirement for Chromatin Remodelling.

Abstract

Base excision repair (BER) is a co-ordinated DNA repair pathway that recognises and repairs chemically modified bases and DNA single strand breaks. It is essential for the maintenance of genome integrity and thus in the prevention of the development of human diseases, including premature ageing, neurodegenerative diseases and cancer. Within the cell, DNA is usually packaged with histone proteins to form chromatin which imposes major constraints on the capacity of cells to perform BER. Therefore chromatin remodelling, stimulated through histone post-translational modifications (PTMs) or ATP-dependent chromatin remodelling complexes (ACRs), are required to stimulate access to the DNA damage and therefore enhance the BER process. Despite this, the molecular mechanisms through which this is co-ordinated and the specific enzymes that promote chromatin remodelling required for BER remain elusive. In this review, we summarise the multitude of in vitro studies utilising mononucleosome substrates containing site-specific DNA base damage that demonstrate the requirement for chromatin remodelling to facilitate BER, particularly in occluded regions. We also highlight preliminary evidence to date for the identity of ACRs, their mechanisms and the role of histone PTMs in modulating the cellular capacity for BER.