Rad5 Plays a Major Role in the Cellular Response to DNA Damage during Chromosome Replication

• Published in: Cell reports (Cambridge) Vol. 9; no. 2; pp. 460 - 468
• Main Authors: Ortiz-Bazán, María Ángeles, Gallo-Fernández, María, Saugar, Irene, Jiménez-Martín, Alberto, Vázquez, María Victoria, Tercero, José Antonio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.10.2014; Elsevier
• Subjects: Chromosomes, Fungal - genetics; DNA Damage; DNA Helicases - genetics; DNA Helicases - metabolism; DNA Replication; Methyl Methanesulfonate - toxicity; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.09.005

The RAD6/RAD18 pathway of DNA damage tolerance overcomes unrepaired lesions that block replication forks. It is subdivided into two branches: translesion DNA synthesis, which is frequently error prone, and the error-free DNA-damage-avoidance subpathway. Here, we show that Rad5HLTF/SHPRH, which mediates the error-free branch, has a major role in the response to DNA damage caused by methyl methanesulfonate (MMS) during chromosome replication, whereas translesion synthesis polymerases make only a minor contribution. Both the ubiquitin-ligase and the ATPase/helicase activities of Rad5 are necessary for this cellular response. We show that Rad5 is required for the progression of replication forks through MMS-damaged DNA. Moreover, supporting its role during replication, this protein reaches maximum levels during S phase and forms subnuclear foci when replication occurs in the presence of DNA damage. Thus, Rad5 ensures the completion of chromosome replication under DNA-damaging conditions while minimizing the risk of mutagenesis, thereby contributing significantly to genome integrity maintenance. [Display omitted] •MMS-induced DNA lesions are mainly tolerated by the error-free Rad5 pathway•Rad5 is required for replication fork progression through MMS-damaged DNA•Rad5 Ub-ligase and ATPase/helicase activities are required for the response to MMS•Rad5 peaks during S phase and forms subnuclear foci in response to DNA damage Ortiz-Bazán et al. now show that tolerance to methyl methanesulfonate (MMS)-induced DNA lesions during S phase is carried out mainly by Rad5-mediated, error-free damage bypass. Rad5 allows the progression of replication forks through MMS-damaged DNA, ensuring the completion of chromosome replication while minimizing mutagenesis, all of which are crucial for genome stability.