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University of Connecticut

Nucleic Acids Res., Feb 28 2024, gkae102 | https://doi.org/10.1093/nar/gkae102 Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer

J ameson R. Av erill^†, Jackson C. Lin^†, John Jung and Hunmin Jung^*

Division of Medicinal Chemistry, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA

^*To whom correspondence should be addressed. : Hunmin Jung

^†The first and second authors should be regarded as Joint First Authors.

Abstract

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 μM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2'-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-07)
연구진국외 연구진
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