HLTF Resolves G4s and Promotes G4-Induced Replication Fork Slowing to Maintain Genome Stability. Gongshi Bai et al.

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G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the dsDNA translocase HLTF in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s in vitro and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, HLTF and MSH2, a component of MutS heterodimers which bind G4s, act independently to suppress G4 accumulation, to restrict alternative lengthening of telomeres and to promote resistance to G4 stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing PrimPol-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevents DNA damage and potentially mutagenic replication to safeguard genome stability. Unprocessed microscopy, gel, and western blot images related to the manuscript are organized by figure numbers. Please refer to the manuscript for details.

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