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How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

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posted on 2023-06-09, 00:03 authored by Penny Jeggo, Markus Lobrich
DNA double-strand breaks (DSBs) 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 utilisation of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. We evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilisation 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 will consider the ways by which cancers modify and accost these processes to gain genomic instability

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Biochemical Journal

ISSN

0264-6021

Publisher

Portland Press

Issue

1

Volume

471

Page range

1-11

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-01-18

First Open Access (FOA) Date

2016-10-01

First Compliant Deposit (FCD) Date

2016-01-18

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