HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal

Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA dam...

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Bibliographic Details
Published in:Molecular cell Vol. 58; no. 6; pp. 1090 - 1100
Main Authors: Kile, Andrew C, Chavez, Diana A, Bacal, Julien, Eldirany, Sherif, Korzhnev, Dmitry M, Bezsonova, Irina, Eichman, Brandt F, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 18.06.2015
Subjects:
Amino Acid Sequence
Base Sequence
Binding Sites - genetics
Blotting, Western
Cell Line, Tumor
Crystallography, X-Ray
DNA - chemistry
DNA - genetics
DNA - metabolism
DNA Replication
DNA, Single-Stranded - chemistry
DNA, Single-Stranded - genetics
DNA, Single-Stranded - metabolism
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Humans
Magnetic Resonance Spectroscopy
Models, Genetic
Models, Molecular
Molecular Sequence Data
Mutation
Nucleic Acid Conformation
Protein Binding
Protein Structure, Tertiary
RNA Interference
Sequence Homology, Amino Acid
Sequence Homology, Nucleic Acid
Transcription Factors - chemistry
Transcription Factors - genetics
Transcription Factors - metabolism
ISSN:1097-4164
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Summary:Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA damage responses in humans is the Rad5-related DNA translocase, HLTF. Here, we present biochemical and structural evidence that the HIRAN domain, an ancient and conserved domain found in HLTF and other DNA processing proteins, is a modified oligonucleotide/oligosaccharide (OB) fold that binds to 3' ssDNA ends. We demonstrate that the HIRAN domain promotes HLTF-dependent fork reversal in vitro through its interaction with 3' ssDNA ends found at forks. Finally, we show that HLTF restrains replication fork progression in cells in a HIRAN-dependent manner. These findings establish a mechanism of HLTF-mediated fork reversal and provide insight into the requirement for distinct fork remodeling activities in the cell.
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ISSN:1097-4164
DOI:10.1016/j.molcel.2015.05.013