SHPRH and HLTF act in a damage-specific manner to coordinate different forms of postreplication repair and prevent mutagenesis

Postreplication repair (PRR) pathways play important roles in restarting stalled replication forks and regulating mutagenesis. In yeast, Rad5-mediated damage avoidance and Rad18-mediated translesion synthesis (TLS) are two forms of PRR. Two Rad5-related proteins, SHPRH and HLTF, have been identified...

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Bibliographic Details
Published in:Molecular cell Vol. 42; no. 2; p. 237
Main Authors: Lin, Jia-Ren, Zeman, Michelle K, Chen, Jia-Yun, Yee, Muh-Ching, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 22.04.2011
Subjects:
Cell Nucleus - drug effects
Cell Nucleus - enzymology
Cell Nucleus - radiation effects
DNA Damage
DNA Helicases - genetics
DNA Helicases - metabolism
DNA Repair
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-Directed DNA Polymerase - metabolism
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
HEK293 Cells
Humans
Methyl Methanesulfonate - pharmacology
Mutagenesis
Mutagens - pharmacology
Proliferating Cell Nuclear Antigen - metabolism
Protein Processing, Post-Translational
Recombinant Fusion Proteins - metabolism
RNA Interference
Transcription Factors - genetics
Transcription Factors - metabolism
Transfection
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Ultraviolet Rays
ISSN:1097-4164, 1097-4164
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Summary:Postreplication repair (PRR) pathways play important roles in restarting stalled replication forks and regulating mutagenesis. In yeast, Rad5-mediated damage avoidance and Rad18-mediated translesion synthesis (TLS) are two forms of PRR. Two Rad5-related proteins, SHPRH and HLTF, have been identified in mammalian cells, but their specific roles in PRR are unclear. Here, we show that HLTF and SHPRH suppress mutagenesis in a damage-specific manner, preventing mutations induced by UV and MMS, respectively. Following UV, HLTF enhances PCNA monoubiquitination and recruitment of TLS polymerase η, while also inhibiting SHPRH function. In contrast, MMS promotes the degradation of HLTF and the interactions of SHPRH with Rad18 and polymerase κ. Our data suggest not only that cells differentially utilize HLTF and SHPRH for different forms of DNA damage, but also, surprisingly, that HLTF and SHPRH may coordinate the two main branches of PRR to choose the proper bypass mechanism for minimizing mutagenesis.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2011.02.026