SHPRH and HLTF Act in a Damage-Specific Manner to Coordinate Different Forms of Postreplication Repair and Prevent Mutagenesis

• Published in: Molecular cell 2011-04, Vol.42 (2), p.237-249
• Main Authors: Lin, Jia-Ren, Zeman, Michelle K., Chen, Jia-Yun, Yee, Muh-Ching, Cimprich, Karlene A.
• Format: Article
• Language: English
• 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; mammals; Methyl Methanesulfonate - pharmacology; MMS; Mutagenesis; Mutagens - pharmacology; proliferating cell nuclear antigen; 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; yeasts
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.02.026

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. [Display omitted] ► HLTF and SHPRH suppress UV- or MMS-induced mutagenesis, respectively ► MMS enhances HLTF degradation and the interactions of SHPRH with Rad18 and Polκ ► HLTF promotes PCNA monoubiquitination and facilitates Polη recruitment post-UV ► HLTF antagonizes SHPRH to suppress UV-induced mutagenesis during DNA replication