Parker, Christopher, Chambers, Adam C, Flanagan, Dustin J, Ho, Jasmine Wing Yu, Collard, Tracey J, Ngo, Greg, Baird, Duncan M, Timms, Penny, Morgan, Rhys G, Sansom, Owen J and Williams, Ann C (2022) BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination. DNA Repair, 115. a103331 1-11. ISSN 1568-7864

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Abstract

The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC), where it has been shown to enhance tumour cell survival. However, although increased expression correlates with poor patient prognosis, the role of BCL-3 in determining therapeutic response remains largely unknown. In this study, we use combined approaches in multiple cell lines and pre-clinical mouse models to investigate the function of BCL-3 in the DNA damage response. We show that suppression of BCL-3 increases γH2AX foci formation and decreases homologous recombination in CRC cells, resulting in reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3-/- mice, where Bcl3-/- mouse crypts also exhibit sensitivity to DNA damage with increased γH2AX foci compared to wild type mice. Additionally, Apc.Kras-mutant x Bcl3-/- mice are more sensitive to cisplatin chemotherapy compared to wild type mice. Taken together, our results identify BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression, as observed in CRC, could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjunct to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Biochemistry
SWORD Depositor:	Mx Elements Account
Depositing User:	Mx Elements Account
Date Deposited:	29 Apr 2022 07:08
Last Modified:	29 Apr 2022 07:15
URI:	http://sro.sussex.ac.uk/id/eprint/105552

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