Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway
Burnet, Neil G
Mackay, Ranald I
Kirkby, Karen J
Merchant, Michael J
AffiliationDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
MetadataShow full item record
AbstractFollowing radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.
CitationIngram SP, Warmenhoven JW, Henthorn NT, Smith EAK, Chadwick AL, Burnet NG, et al. Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway. Sci Rep. 2019; 9(1):6359.
- The pendulum of the Ku-Ku clock.
- Authors: Shibata A, Jeggo P, Löbrich M
- Issue date: 2018 Nov
- Repair pathway choice for double-strand breaks.
- Authors: Xu Y, Xu D
- Issue date: 2020 Jul 10
- Regulation of DNA double-strand break repair pathway choice.
- Authors: Shrivastav M, De Haro LP, Nickoloff JA
- Issue date: 2008 Jan
- Nonhomologous End-Joining with Minimal Sequence Loss Is Promoted by the Mre11-Rad50-Nbs1-Ctp1 Complex in <i>Schizosaccharomyces pombe</i>.
- Authors: Li Y, Wang J, Zhou G, Lajeunesse M, Le N, Stawicki BN, Corcino YL, Berkner KL, Runge KW
- Issue date: 2017 May
- Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks.
- Authors: Langerak P, Mejia-Ramirez E, Limbo O, Russell P
- Issue date: 2011 Sep