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During replication, DNA polymerase \u03b3 (Pol\u03b3) must traverse duplex junctions and stable secondary structures, yet how the human enzyme overcomes these barriers remains incompletely understood. Here, cryo-electron microscopy structures of Pol\u03b3 bound to forked DNA, G-quadruplex (G4)-containing DNA and DNA bound to mitochondrial single-stranded DNA-binding protein (mtSSB) reveal a common template-entry path along the catcher domain across distinct substrate and active-site configurations. Within this domain, an arginine-rich helix containing R1026, R1030 and R1034 constitutes a Template Stabilising Motif (TSM). Biochemical reconstitution and DNA-binding experiments show that disrupting the TSM selectively impairs strand displacement, RNA-DNA hybrid displacement and synthesis through G4-forming sequences, while largely preserving synthesis on unstructured templates. Single-molecule optical-tweezers experiments further show that mechanical destabilisation of the fork partially restores mutant strand-displacement activity, whereas force or mtSSB restores primer-extension kinetics on ssDNA templates. Together, these findings establish the role of the TSM in maintaining productive template engagement and identify template stabilisation as a common mechanism enabling Pol\u03b3 to traverse structurally diverse barriers in mtDNA.<\/jats:p>","DOI":"10.64898\/2026.09.27.754746","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:50:29Z","timestamp":1790607029000},"source":"Crossref","is-referenced-by-count":0,"title":["A dedicated motif in human polymerase gamma enables DNA synthesis through replication roadblocks"],"prefix":"10.64898","author":[{"given":"Samuel","family":"Miguez-Amil","sequence":"first","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Araceli","family":"Grande-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Plaza G.A.","family":"Ismael","sequence":"additional","affiliation":[{"name":"IMDEA Nanoscience, Cantoblanco, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Moreno-Morcillo","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Casaj\u00fas-Pelegay","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Arean-Ulloa","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Chac\u00f3n-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grzegorz L.","family":"Ciesielski","sequence":"additional","affiliation":[{"name":"Department of Biology, University of North Florida, Jacksonville, FL, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borja","family":"Ibarra","sequence":"additional","affiliation":[{"name":"IMDEA Nanoscience, Cantoblanco, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7941-0357","authenticated-orcid":false,"given":"Rafael","family":"Fernandez-Leiro","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102622051930000_2026.09.27.754746v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.07.004"},{"key":"2026102622051930000_2026.09.27.754746v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3275"},{"key":"2026102622051930000_2026.09.27.754746v2.3","unstructured":"Copeland, W. 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