The role of TREX1 and TREX2 in cellular responses to cisplatin

Cisplatin is a platinum-based chemotherapeutic agent that is used in the treatment of multiple cancer types including hepatocellular carcinoma, osteosarcoma and ovarian cancer, yet the development of resistance remains a significant barrier to therapy success. Resistance to cisplatin is commonly mediated by alterations in the DNA damage response (DDR), a complex network of biochemical pathways that maintains genome integrity. Despite extensive research, few DDR inhibitors have been approved for combination with cisplatin. This study aimed to identify novel DDR targets to enhance cisplatin-induced cell death in cancer cells. Transcriptomic profiling of cisplatin-treated cancer cells identified the 3’ to 5’ exonucleases TREX1 and TREX2 as significantly upregulated DDR genes. Increased expression was confirmed at the protein level in two distinct cancer cell lines. Individual depletion of TREX1 and TREX2 had no effect on cell viability under basal conditions but caused increased G2/M accumulation. Following cisplatin treatment, TREX1 or TREX2 knockdown reduced cisplatin-induced cell death and DNA damage signalling, with fewer cells in S-phase and more cells in G2/M. Co-immunoprecipitation identified CDK1 as an interacting partner of both TREX1 and TREX2, potentially linking these exonucleases to cell cycle regulation. Notably, dual depletion of TREX1 and TREX2 caused significant cell death under basal conditions and overcame the reduced cisplatin sensitivity caused by individual depletion of these proteins. Dual depletion also significantly enhanced cisplatin-induced cell death in HepG2 cells but not U2OS cells and was accompanied by loss of the G2/M accumulation observed with individual depletion and restoration of the level of cisplatin- induced γH2AX-positive cells. Multi-omic analysis of CRISPR/Cas9-mediated single and double knockout cells revealed widespread DDR suppression and enhanced activation of innate immune pathways following loss of TREX1 and/or TREX2 and cisplatin treatment. Additionally, combined TREX1 and TREX2 depletion caused phosphorylation of eIF2α, indicating activation of the integrated stress response. These findings identify TREX1 and TREX2 as potential DDR targets and suggest that targeting both proteins could enhance cisplatin sensitivity in specific cancer types.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2026

Author dc:creator

• Ahmed Nur, Hashim

Advisors dc:contributor.advisor

• Aitken, Sarah
• Willis, Anne
• MacFarlane, Marion

• Chemotherapy resistance
• DNA damage response
• DNA repair
• Multi-omics
• Cancer research

Licence

• https://www.repository.cam.ac.uk/bitstreams/bc47a441-f1a1-42c0-afbc-2ecc3bf528cf/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.130476

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/403607