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Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Pol\u03b4 is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Pol\u03b7 is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Pol\u03b7 with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Pol\u03b7 can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Pol\u03b7 to promote AraC induced mutagenesis in relapsed AML patients.<\/jats:p>","DOI":"10.1038\/s41598-019-52703-7","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T14:48:06Z","timestamp":1573224486000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase \u03b7"],"prefix":"10.1038","volume":"9","author":[{"given":"Olga","family":"Rechkoblit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Buku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneel K.","family":"Aggarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,8]]},"reference":[{"key":"52703_CR1","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1182\/blood-2017-04-777722","volume":"130","author":"KN Magina","year":"2017","unstructured":"Magina, K. 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