Physical interactions between specifically regulated subpopulations of the MCM and RNR complexes prevent genetic instability

• Published in: PLoS genetics 2024-05, Vol.20 (5), p.e1011148-e1011148
• Main Authors: Yáñez-Vilches, Aurora, Romero, Antonia M, Barrientos-Moreno, Marta, Cruz, Esther, González-Prieto, Román, Sharma, Sushma, Vertegaal, Alfred C O, Prado, Félix
• Format: Article
• Language: English
• Subjects: Analysis; Biology and life sciences; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Coordination compounds; Cyclin-dependent kinases; DNA biosynthesis; DNA damage; DNA Damage - genetics; DNA helicase; DNA Helicases - genetics; DNA Helicases - metabolism; DNA repair; DNA Repair - genetics; DNA replication; DNA Replication - genetics; Genomes; Genomic Instability; Helicases; Identification and classification; Kinases; Mass spectrometry; Minichromosome Maintenance Proteins - genetics; Minichromosome Maintenance Proteins - metabolism; Phenotypes; Phosphorylation; Physiological aspects; Properties; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Rad52 DNA Repair and Recombination Protein - genetics; Rad52 DNA Repair and Recombination Protein - metabolism; Rad52 protein; Replication Protein A - genetics; Replication Protein A - metabolism; Research and Analysis Methods; Ribonucleoside Diphosphate Reductase - genetics; Ribonucleoside Diphosphate Reductase - metabolism; Ribonucleotide reductase; Ribonucleotide Reductases - genetics; Ribonucleotide Reductases - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Scientific imaging; Subpopulations; Yeast
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1011148

The helicase MCM and the ribonucleotide reductase RNR are the complexes that provide the substrates (ssDNA templates and dNTPs, respectively) for DNA replication. Here, we demonstrate that MCM interacts physically with RNR and some of its regulators, including the kinase Dun1. These physical interactions encompass small subpopulations of MCM and RNR, are independent of the major subcellular locations of these two complexes, augment in response to DNA damage and, in the case of the Rnr2 and Rnr4 subunits of RNR, depend on Dun1. Partial disruption of the MCM/RNR interactions impairs the release of Rad52 -but not RPA-from the DNA repair centers despite the lesions are repaired, a phenotype that is associated with hypermutagenesis but not with alterations in the levels of dNTPs. These results suggest that a specifically regulated pool of MCM and RNR complexes plays non-canonical roles in genetic stability preventing persistent Rad52 centers and hypermutagenesis.