BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination

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

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (4MB)


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

View download statistics for this item

📧 Request an update