DNA damage and cell cycle regulation of ribonucleotide reductase

摘要

AbstractRibonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, includingE. coli, S. cerevisiaeandH. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational repair processes.S. cerevisiaealso encodes a second large subunit gene,RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response inS. cerevisiaehas shown thatRNRexpression is under both positive and negative control. Among mutants constitutive forRNRexpression are the general transcriptional repression genes,SSN6andTUP1. Mutations inPOL1andPOL3also activateRNRexpression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility ofRNR1, RNR2andRNR3in response to DNA damage and replication blocks. This result suggests that theRNRgenes inS. cerevisiaeform a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage.