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Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>DNA replication is an exquisitely regulated process that requires tight coordination at the eukaryotic replication fork, operating within the compacted chromatin environment. Minimizing exposure of naked DNA is critical to prevent nuclease degradation and genome instability, a hallmark of cancer. Cells, therefore, require a surveillance mechanism that links nucleosome assembly status to DNA replication. Here, we show that histone H3-H4 delivered by the chaperone facilitates chromatin transaction (FACT) directly stimulates the DNA polymerase activity of the polymerase \u03b1 (Pol \u03b1, primase-polymerase complex) at replication forks. Histone H3-H4, but not histone H2A-H2B, promotes assembly of a FACT\u2013(H3-H4)\u2013Pol1 complex in S phase, where FACT associates with the Pol1 catalytic subunit in an H3-H4\u2013dependent manner. This H3-H4\u2013bridged interaction enhances Pol \u03b1 primer extension on both DNA- and RNA-primed templates, increasing synthesis rate without altering primer patterning. Mechanistically, the Pol1 N-terminal domain, particularly its \u03b11 and \u03b12 helices, mediates complex assembly; the Pol1-\u0394\u03b11\u03b12 mutation disrupts this interaction and impairs primer extension in vitro. In cells, disrupting this complex reduces Okazaki fragment synthesis and slows replication fork progression. Among replication-coupled histone chaperones, only FACT interacts with Pol \u03b1, and this association is attenuated when chromatin assembly factor 1 (CAF-1)\u2013 and regulator of Ty1 transposition protein 106 (Rtt106)\u2013dependent nucleosome assembly is compromised. Together, our results support a model whereby the FACT\u2013(H3-H4)\u2013Pol \u03b1 complex serves as a sensor of H3-H4 availability, coordinating DNA synthesis with replication-coupled nucleosome assembly to safeguard genome stability.<\/jats:p>","DOI":"10.1126\/sciadv.aeh7889","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:58:53Z","timestamp":1790359133000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["FACT\u2013(H3-H4) complex stimulates Pol \u03b1 activity to coordinate DNA synthesis with nucleosome assembly"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-0344","authenticated-orcid":true,"given":"Wenshuo","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Protein and Gene Modulation Research, School of Life Sciences, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 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