DNA damage and cell cycle regulation of ribonucleotide reductase

✍ Scribed by Stephen J. Elledge; Zheng Zhou; James B. Allen; Tony A. Navas

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: English
• Weight: 840 KB
• Volume: 15
• Category: Article
• ISSN: 0265-9247
• DOI: 10.1002/bies.950150507

✦ Synopsis

Kihonucleotide 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. niRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H . sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational repair processes. S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNK expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression gencs, SSNd and TUPl. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dunl, has been identified that controls inducibility of RNRl, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in responsc to DNA damage. 42 Weinert, T.A. and Hartwell, I,.H. (19XXI. 'r response to DNAdaiiiagc in . S u i ~r ~h ~i r n ~~z ~~. r s w r 43 Devray, Y., Gottlieb. R.A.. Smeal, T. and Karin, M ( I 992). 'I he mammalian ultraviolet response IS triggered hy activation of Src tyrosine kinase. Cell 71. 1081-1Oc)l.