Work

F10 cytotoxicity via topoisomerase I cleavage complex repair consistent with a unique mechanism for thymineless death

Year: 2024

Type: article

Abstract: DNA topoisomerase I (Top1) is the sole target of camptothecin (CPT) and other Top1 poisons [1] that are widely used drugs for treatment of colon cancer and other malignancies. Our previous studies have shown that Top1 is also an important target for the fluoropyrimidine polymer F10 reviewed in [2], and that Top1 poisoning plays an important, but relatively undefined role in thymineless death (TLD), the process by which inhibiting de novo thymidylate synthesis causes DNA damage and cell death. While Top1 poisoning is an important aspect of TLD, thymidine deprivation may also cause DNA damage by Top1-independent pathways, such as replication fork collapse, and these multiple sources of DNA damage may provide the basis for the very strong potency of F10 relative to alternative DNA damaging agents observed for many types of malignant cells. Elucidating the DNA repair pathways activated in cells treated with F10 relative to CPT can provide insight into how Top1 poisoning induced by fluoropyrimidine drugs differs from traditional Top1 poisons, and also clarify which aspects of the DNA damage response are activated by Top1-independent processes.

Source: Carolina Digital Repository (University of North Carolina at Chapel Hill)

DOI: 10.17615/nrcj-g935

Authors: Nakamura, Jun, Gearhart, Patricia J, Gmeiner, William H, Pommier, Yves

Institution: University of North Carolina at Chapel Hill

Language: English

Topic: Cancer therapeutics and mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institute on Aging, National Institute of Environmental Health Sciences