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

Published: 13 August 2024| Version 1 | DOI: 10.17632/bb6sg2k5ck.1
Contributors:
Karlene Cimprich,

Description

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.

Files

Institutions

Universita della Svizzera Italiana, Francis Crick Institute, Stanford University, Vanderbilt University

Categories

Biochemistry, Molecular Biology, Cell Biology, Fluorescence Microscopy

Funding

National Institutes of Health

P01CA092584

National Institutes of Health

ES016486

National Institutes of Health

R35GM136401

National Institutes of Health

R01GM116616

European Research Council

Advanced Grant 101018257

Swiss Cancer Research Foundation

KFS-5397-08-2021

EMBO

ALTF-710-2021

Francis Crick Institute

CC2098

Wellcome

225139/Z/22/Z

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

310030_207588

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

310030_205199

American Cancer Society

UK Research and Innovation

European Research Council

Cancer Research UK

Wellcome Trust

National Institutes of Health

S10OD026899

EMBO

ALTF-696-2022

Novo Nordisk Fonden

NNF23OC0083126

Licence