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HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability.

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posted on 2024-11-04, 12:09 authored by Gongshi Bai, Theresa Endres, Ulrike Kühbacher, Valentina Mengoli, Briana H Greer, Emma M Peacock, Matthew D Newton, Tyler Stanage, Maria Rosaria Dello Stritto, Roxana Lungu, Magdalena P Crossley, Ataya Sathirachinda, David Cortez, Simon J Boulton, Petr Cejka, Brandt F Eichman, Karlene A Cimprich
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 double-stranded DNA (dsDNA) translocase helicase-like transcription factor (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, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.

Funding

Crick (Grant ID: CC2057, Grant title: Boulton CC2057) European Research Council (Grant ID: 742437 - TelMetab, Grant title: ERC 742437 - TelMetab) Wellcome Trust (Grant ID: 225139/Z/22/Z, Grant title: WT 225139/Z/22/Z)

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