Chromatin and the DNA damage response: the cancer connection.

Abstract

The integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management.