DNA Damage Response: From Tumourigenesis to Therapy

Abstract

Abstract The deoxyribonucleic acid (DNA) damage response (DDR) pathway is a surveillance network, whereby lesions are eliminated from DNA to ensure genomic integrity. The DDR detects aberrant DNA and chromosomal structures and elicits a multifaceted response network to coordinate multiple cellular processes, including regulation of the cell cycle, DNA repair, replication and, under certain circumstances, the triggering of programmed cell death. However, when the DDR is dysregulated, genomic integrity is not ensured, which may lead to tumourigenesis. Paradoxically, although genomic instability is a hallmark of many cancers, many conventional cancer treatments elicit the generation of additional DNA damage to exploit inherent DDR faults present in tumour cells. In addition, new‐targeted DDR inhibitors are currently being developed to enhance therapeutic indexes, including those that are synthetically lethal in particular tumour cell types, providing exciting new therapeutic avenues for cancer treatment. The challenge is how to identify the patients most receptive to these treatments. Key Concepts: Genome stability is critical to prevent tumourigenesis. Cell cycle checkpoints and DNA repair exist to prevent faulty genetic information from passing onto daughter cells. Many cancer types exhibit defective DNA repair pathways. DNA repair is an ideal therapeutic target for cancer. Cancers exhibit multiple chromosomal alterations. Inherited mutations in DNA repair genes can cause chromosomal instability disorders.