title: How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability.
abstract: DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, U.K. p.a.jeggo@sussex.ac.uk lobrich@bio.tu-darmstadt.de.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.affiliation: Darmstadt University of Technology, Radiation Biology and DNA Repair, 64287 Darmstadt, Germany p.a.jeggo@sussex.ac.uk lobrich@bio.tu-darmstadt.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Löbrich
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
keywords: alternative NHEJ; cancer cells; double-strand break repair; genomic stability; homologous recombination; non-homologous end-joining