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Here, we directly compare full-length hPIF1 and budding yeast Pif1 (yPif1) and show that the two enzymes operate differently. In bulk assays, hPIF1 displays weak net DNA unwinding because its robust intrinsic single-stranded DNA (ssDNA) annealing activity rapidly reforms duplex DNA behind the helicase motor. Single-molecule magnetic tweezers experiments reveal that hPIF1 is only modestly slower than yPif1 and similarly processive, indicating that poor apparent unwinding primarily reflects rapid reannealing rather than impaired motor activity. Mutagenesis and structural modeling indicate that this functional divergence depends on a yeast-specific insertion within the catalytic domain. Unlike yPif1, hPIF1 fails to stimulate Pol\u03b4-dependent displacement-loop (D-loop) extension, arguing that it does not promote DNA unwinding ahead of the migrating bubble. However, similarly to yPif1, hPIF1 likely unwinds newly synthesized DNA coupled with DNA reannealing behind the migrating D-loop. hPIF1 efficiently remodels intramolecular G-quadruplex DNA into fully base-paired dsDNA, whereas yPif1 generates ssDNA products. Together, our data support a model in which hPIF1 acts primarily as a DNA translocase that couples local unwinding with rapid rewinding to clear secondary DNA structures without generating extensive ssDNA.<\/jats:p>","DOI":"10.1101\/gad.353775.126","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T17:15:16Z","timestamp":1786382116000},"page":"1747-1764","source":"Crossref","is-referenced-by-count":0,"title":["Human PIF1 clears secondary DNA structures by coupled DNA unwinding and rewinding activities"],"prefix":"10.1101","volume":"40","author":[{"given":"Akshay","family":"Jayachandran","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Universit\u00e0 della Svizzera italiana (USI), Bellinzona 6500, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"M\u00fctze","sequence":"additional","affiliation":[{"name":"Peter Debye Institute for Soft 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