{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:17:02Z","timestamp":1788218222636,"version":"build-2803163510"},"reference-count":73,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["30631"],"award-info":[{"award-number":["30631"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>DNA polymerases (Pols) are essential enzymes for DNA replication within the cell. However, DNA lesions, such as cyclobutane pyrimidine dimers (CPDs) induced by ultraviolet (UV) radiation, can impair Pols\u2019s function and DNA replication. Therefore, the presence of CPDs can, for example, lead to xeroderma pigmentosum variant (XP-V), a rare genetic disorder characterized by an increased risk of skin cancer. Nonetheless, in these situations, specific translesion synthesis (TLS) Pols, such as human DNA polymerase \u03b7 (Pol\u03b7), can overcome such lesions, enabling DNA polymerization. That is, Pol\u03b7 prevents the pathological risks associated with CPD-caused DNA replication stalling. Here, we analyzed how a selected set of 8 Pol\u03b7 mutations perturbs its structure, DNA binding, and substrate translocation, thereby altering Pol\u03b7 function, preventing it from bypassing CPDs, thus making them XP-V pathogenic mutations. Leveraging recent structural and clinical data on these pathogenic Pol\u03b7 variants, we elucidated the mechanistic basis for their impairment of Pol\u03b7\u2032s ability to bypass damage. We employed molecular dynamics simulations to examine their effects on Pol\u03b7 in pre- and post-translocation states. Although these residues vary in location and chemical nature, we found that all contributed to reducing DNA anchoring to Pol\u03b7. In this way, we could identify a unified mechanistic framework for decoding how XP-V pathogenic mutations compromise Pol\u03b7 function by destabilizing the Pol\u03b7\u2013DNA complex.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c00345","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T19:57:59Z","timestamp":1779393479000},"page":"8566-8578","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Cancer-Associated Mutations in DNA Polymerase\n\u03b7 through Atomistic Simulations"],"prefix":"10.1021","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-893X","authenticated-orcid":true,"given":"Alessia","family":"Visigalli","sequence":"first","affiliation":[{"name":"Istituto Italiano di Tecnologia , , Via Enrico Melen 83 , ,","place":["Genoa, Italy, 16142"]},{"name":"Forschungszentrum Ju\u0308lich GmbH , , ,","place":["Ju\u0308lich, Germany, 52428"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-0149","authenticated-orcid":true,"given":"Paolo","family":"Carloni","sequence":"additional","affiliation":[{"name":"Forschungszentrum Ju\u0308lich GmbH , , ,","place":["Ju\u0308lich, Germany, 52428"]},{"name":"RWTH Aachen University , , ,","place":["Aachen, Germany, 52056"]},{"name":"Forschungszentrum Ju\u0308lich GmbH , , ,","place":["Ju\u0308lich, Germany, 09042"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-5661","authenticated-orcid":true,"given":"Marco","family":"De Vivo","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia , , Via Enrico Melen 83 , ,","place":["Genoa, Italy, 16142"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"2026083118573651500_cit1","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nrg2345","article-title":"DNA Polymerases\nand Human Disease","volume":"9","author":"Loeb","year":"2008","journal-title":"Nat. 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Rev.\nBiochem."},{"key":"2026083118573651500_cit4","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1021\/bi500019s","article-title":"An Overview\nof Y-Family DNA Polymerases and a Case Study of Human DNA Polymerase\n\u03b7","volume":"53","author":"Yang","year":"2014","journal-title":"Biochemistry"},{"issue":"2","key":"2026083118573651500_cit5","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nrc2998","article-title":"DNA Polymerases and Cancer","volume":"11","author":"Lange","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"2026083118573651500_cit6","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/978-90-481-3471-7_10","article-title":"Genome Stability and Human Diseases","volume":"50","author":"Cruet-Hennequart","year":"2010","journal-title":"Subcell. 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Mutagen."},{"key":"2026083118573651500_cit8","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/nature11181","article-title":"Watching DNA\nPolymerase \u03b7 Make a Phosphodiester Bond","volume":"487","author":"Nakamura","year":"2012","journal-title":"Nat."},{"key":"2026083118573651500_cit9","doi-asserted-by":"publisher","first-page":"11103","DOI":"10.1021\/acscatal.8b03363","article-title":"The Catalytic\nMechanism of DNA and\nRNA Polymerases","volume":"8","author":"Genna","year":"2018","journal-title":"ACS Catal."},{"issue":"6","key":"2026083118573651500_cit10","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1534","article-title":"Computational\nInvestigations\nof Polymerase Enzymes: Structure, Function, Inhibition, and Biotechnology","volume":"11","author":"Geronimo","year":"2021","journal-title":"Wiley Interdiscip. Rev.:Comput. Mol. 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Dermatol."},{"key":"2026083118573651500_cit30","doi-asserted-by":"publisher","first-page":"115044","DOI":"10.1016\/j.ejmech.2022.115044","article-title":"Computer-Aided Identification, Synthesis, and Biological\nEvaluation of DNA Polymerase \u03b7 Inhibitors for the Treatment\nof Cancer","volume":"248","author":"Munafo\u0300","year":"2023","journal-title":"Eur. J. Med. Chem."},{"issue":"7","key":"2026083118573651500_cit31","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1021\/acs.biochem.7b01176","article-title":"A Small-Molecule\nInhibitor of Human DNA Polymerase \u03b7 Potentiates the Effects\nof Cisplatin in Tumor Cells","volume":"57","author":"Zafar","year":"2018","journal-title":"Biochemistry"},{"key":"2026083118573651500_cit32","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1021\/acs.jcim.2c01430","article-title":"On the Role of Molecular Conformation\nof the 8-Oxoguanine Lesion in Damaged DNA Processing by Polymerases","volume":"63","author":"Geronimo","year":"2023","journal-title":"J. Chem. Inf. Model."},{"issue":"13","key":"2026083118573651500_cit33","doi-asserted-by":"publisher","first-page":"5285","DOI":"10.1021\/acs.jcim.4c00696","article-title":"Correct Nucleotide\nSelection Is Confined at the Binding Site of Polymerase Enzymes","volume":"64","author":"Figueroa Blanco","year":"2024","journal-title":"J. Chem. Inf. Model."},{"issue":"33","key":"2026083118573651500_cit34","doi-asserted-by":"publisher","first-page":"10955","DOI":"10.1021\/ja8005786","article-title":"Phosphodiester Cleavage in Ribonuclease\nH Occurs via an Associative Two-Metal-Aided Catalytic Mechanism","volume":"130","author":"De Vivo","year":"2008","journal-title":"J. Am. Chem. Soc."},{"issue":"9","key":"2026083118573651500_cit35","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of Molecular Dynamics\nand Related Methods in Drug Discovery","volume":"59","author":"De Vivo","year":"2016","journal-title":"J. Med.\nChem."},{"issue":"12","key":"2026083118573651500_cit36","doi-asserted-by":"publisher","first-page":"6781","DOI":"10.1021\/acs.jctc.9b00697","article-title":"Bridge: A Graph-Based Algorithm to Analyze Dynamic\nH-Bond Networks in Membrane Proteins","volume":"15","author":"Siemers","year":"2019","journal-title":"J. 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Biol."},{"issue":"23","key":"2026083118573651500_cit40","doi-asserted-by":"publisher","first-page":"13825","DOI":"10.1021\/acscatal.0c04148","article-title":"Functional\nImplications of Second-Shell\nBasic Residues for dUTPase DR2231 Enzymatic Specificity","volume":"10","author":"Vidossich","year":"2020","journal-title":"ACS Catal."},{"key":"2026083118573651500_cit41","doi-asserted-by":"publisher","first-page":"3747","DOI":"10.1074\/jbc.M115.706226","article-title":"Mechanism of Ribonucleotide Incorporation\nby Human DNA Polymerase \u03b7","volume":"291","author":"Su","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026083118573651500_cit42","doi-asserted-by":"publisher","first-page":"102938","DOI":"10.1016\/j.jbc.2023.102938","article-title":"Primer Terminal Ribonucleotide Alters the Active Site Dynamics of\nDNA Polymerase \u03b7 and Reduces DNA Synthesis Fidelity","volume":"299","author":"Chang","year":"2023","journal-title":"J. Biol. 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Res. Toxicol."},{"issue":"10","key":"2026083118573651500_cit48","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1021\/acs.chemrestox.6b00244","article-title":"Six Germline Genetic Variations Impair\nthe Translesion Synthesis Activity of Human DNA Polymerase \u03ba","volume":"29","author":"Kim","year":"2016","journal-title":"Chem. Res. Toxicol."},{"issue":"3","key":"2026083118573651500_cit49","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative Protein\nModelling by Satisfaction of Spatial\nRestraints","volume":"234","author":"Sali","year":"1993","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026083118573651500_cit50","doi-asserted-by":"publisher","first-page":"5.6.1","DOI":"10.1002\/cpbi.3","article-title":"Comparative Protein Structure Modeling\nUsing MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. 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A.; Kasavajhala, K.; Kaymak, M. C.; ry, I. K.; Kovalenko, A.; Kurtzman, T.; Lee, T. S.; Li, P.; Li, Z.; Lin, C.; Liu, J.; Luchko, T.; Luo, R.; Machado, M.; Manathunga, M.; Merz, K. M.; Miao, Y.; Mikhailovskii, O.; Monard, G.; Nguyen, H.; O\u2019Hearn, K. A.; Onufriev, A.; Pan, F.; Pantano, S.; Rahnamoun, A.; Roe, D. R.; Roitberg, A.; Sagui, C.; Schott-Verdugo, S.; Shajan, A.; Shen, J.; Simmerling, C. L.; Skrynnikov, N. R.; Smith, J.; Swails, J.; Walker, R. C.; Wang, J.; Wang, J.; Wu, X.; Wu, Y.; Xiong, Y.; Xue, Y.; York, D. M.; Zhao, C.; Zhu, Q.; Kollman; ; Amber, P. A.\n          Reference Manual 2024, 2024."},{"issue":"2","key":"2026083118573651500_cit54","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An Overview\nof the Amber Biomolecular\nSimulation Package","volume":"3","author":"Salomon-Ferrer","year":"2013","journal-title":"Wiley Interdiscip. Rev.:Comput.\nMol. 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