Reference: Dyavaiah M, et al. (2011) Autophagy-Dependent Regulation of the DNA Damage Response Protein Ribonucleotide Reductase 1. Mol Cancer Res 9(4):462-475

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Abstract

Protein synthesis and degradation are post-transcriptional pathways used by cells to regulate protein levels. We have developed a systems biology approach to identify targets of post-transcriptional regulation and we have employed this system in S. cerevisiae to study the DNA damage response. We present evidence that 50 - 75% of the transcripts induced by alkylation damage are regulated post-transcriptionally. Significantly, we demonstrate that two transcriptionally-induced DNA damage response genes, RNR1 and RNR4, fail to show soluble protein level increases after DNA damage. To determine one of the associated mechanisms of post-transcriptional regulation, we tracked ribonucleotide reductase 1 (Rnr1) protein levels during the DNA damage response. We show that RNR1 is actively translated after damage, and that a large fraction of the corresponding Rnr1 protein is packaged into a membrane-bound structure and transported to the vacuole for degradation, with these last two steps dependent on autophagy proteins. We found that inhibition of target of rapamycin (TOR) signaling and subsequent induction of autophagy promoted an increase in targeting of Rnr1 to the vacuole and a decrease in soluble Rnr1 protein levels. Additionally, we demonstrate that defects in autophagy result in an increase in soluble Rnr1 protein levels and a DNA damage phenotype. Our results highlight roles for autophagy and TOR signaling in regulating a specific protein and demonstrate the importance of these pathways in optimizing the DNA damage response.

Reference Type
Journal Article
Authors
Dyavaiah M, Rooney J, Chittur SV, Lin QS, Begley T
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