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Fast-growing cells including cancer cells have high demand for nucleotide, and they highly utilize the nucleotide biosynthesis pathways. Due to the nature of the fast-growing cells, they tend to make more errors in replication compared with the normal cells. Naturally, DNA repair and DNA lesion bypass are heavily employed in cancer cells to ensure fidelity and completion of the replication without stalling. There have been a lot of drugs targeting cancer that mimic the chemical structures of the nucleobase, nucleoside, and nucleotides, and the resistance toward those drugs is a serious problem. Herein, we have reviewed some of the representative nucleotide analog anticancer agents such as 5-fluorouracil, specifically their mechanism of action and resistance is discussed. Also, we have chosen several enzymes in nucleotide biosynthesis, DNA repair, and DNA lesion bypass, and we have discussed the known and potential roles of these enzymes in maintaining genomic fidelity and cancer chemotherapy.<\/jats:p>","DOI":"10.1042\/bsr20231382","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T12:02:22Z","timestamp":1724760142000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Connecting dots between nucleotide biosynthesis and DNA lesion repair\/bypass in cancer"],"prefix":"10.1042","volume":"44","author":[{"given":"Jackson\u00a0C.","family":"Lin","sequence":"first","affiliation":[{"name":"The Division of Medicinal Chemistry, School of Pharmacy, The University of Connecticut, Storrs, Connecticut 06269, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayobami","family":"Oludare","sequence":"additional","affiliation":[{"name":"The Division of Medicinal Chemistry, School of Pharmacy, The University of Connecticut, Storrs, Connecticut 06269, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8171-0412","authenticated-orcid":false,"given":"Hunmin","family":"Jung","sequence":"additional","affiliation":[{"name":"The Division of Medicinal Chemistry, School of Pharmacy, The University of Connecticut, Storrs, Connecticut 06269, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"2024092305465452100_B1","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1093\/annonc\/mdh264","article-title":"5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers","volume":"15","author":"Noordhuis","year":"2004","journal-title":"Ann. 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