HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis

DNA replication stress can stall replication forks, leading to genome instability. DNA damage tolerance pathways assist fork progression, promoting replication fork reversal, translesion DNA synthesis (TLS), and repriming. In the absence of the fork remodeler HLTF, forks fail to slow following repli...

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Bibliographic Details
Published in:Molecular cell Vol. 78; no. 6; p. 1237
Main Authors: Bai, Gongshi, Kermi, Chames, Stoy, Henriette, Schiltz, Carl J, Bacal, Julien, Zaino, Angela M, Hadden, M Kyle, Eichman, Brandt F, Lopes, Massimo, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 18.06.2020
Subjects:
Cell Line, Tumor
DNA - biosynthesis
DNA - genetics
DNA Damage - genetics
DNA Primase - metabolism
DNA Primase - physiology
DNA Repair - genetics
DNA Replication - genetics
DNA Replication - physiology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-Directed DNA Polymerase - metabolism
DNA-Directed DNA Polymerase - physiology
HEK293 Cells
Humans
K562 Cells
Multifunctional Enzymes - metabolism
Multifunctional Enzymes - physiology
Nucleotidyltransferases - metabolism
Nucleotidyltransferases - physiology
Transcription Factors - genetics
Transcription Factors - metabolism
DNA replication, replication stress response, fork reversal, HLTF, PRIMPOL, REV1, DNA damage tolerance, translesion synthesis, ATR inhibition, replication catastrophe
ISSN:1097-4164, 1097-4164
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Summary:DNA replication stress can stall replication forks, leading to genome instability. DNA damage tolerance pathways assist fork progression, promoting replication fork reversal, translesion DNA synthesis (TLS), and repriming. In the absence of the fork remodeler HLTF, forks fail to slow following replication stress, but underlying mechanisms and cellular consequences remain elusive. Here, we demonstrate that HLTF-deficient cells fail to undergo fork reversal in vivo and rely on the primase-polymerase PRIMPOL for repriming, unrestrained replication, and S phase progression upon limiting nucleotide levels. By contrast, in an HLTF-HIRAN mutant, unrestrained replication relies on the TLS protein REV1. Importantly, HLTF-deficient cells also exhibit reduced double-strand break (DSB) formation and increased survival upon replication stress. Our findings suggest that HLTF promotes fork remodeling, preventing other mechanisms of replication stress tolerance in cancer cells. This remarkable plasticity of the replication fork may determine the outcome of replication stress in terms of genome integrity, tumorigenesis, and response to chemotherapy.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2020.04.031