Cellular Responses to DNA Damage: Translating Mechanistic Insights Towards New Therapies

Abstract

All organisms possess DNA repair and associated DNA damage response (DDR) mechanisms to detect, signal and repair diverse forms of DNA damage. In addition to their fundamental importance for myriad aspects of cell physiology, DDR processes also have medical importance, as underlined by their deregulation or inactivation causing developmental defects, cancer predisposition, stem-cell exhaustion, infertility, immune-deficiencies, inflammation, neurodegeneration and/or premature ageing. New DDR proteins and regulators undoubtedly await discovery. Moreover, we still only have a rudimentary understanding of how human DDR components functionally connect as a network and are regulated by factors including cell-cycle stage, transcription, replication, chromatin, drugs and physiological stress. We also currently lack accurate and predictive models for DDR processes and how their functions connect to health and disease. In this chapter, I briefly survey the various forms of DNA damage and explain the general principles and processes by which cells respond to and repair them. I then go on to explain how our increasing knowledge of such processes is providing insights into human disease mechanisms, and is also paving the way for the development of new drugs, including some that are already extending the lives of cancer patients worldwide.