title: Distinct roles of yeast MEC and RAD checkpoint genes in transcriptional induction after DNA damage and implications for function.
abstract: In eukaryotic cells, checkpoint genes cause arrest of cell division when DNA is damaged or when DNA replication is blocked. In this study of budding yeast checkpoint genes, we identify and characterize another role for these checkpoint genes after DNA damage-transcriptional induction of genes. We found that three checkpoint genes (of six genes tested) have strong and distinct roles in transcriptional induction in four distinct pathways of regulation (each defined by induction of specific genes). MEC1 mediates the response in three transcriptional pathways, RAD53 mediates two of these pathways, and RAD17 mediates but a single pathway. The three other checkpoint genes (including RAD9) have small (twofold) but significant roles in transcriptional induction in all pathways. One of the pathways that we identify here leads to induction of MEC1 and RAD53 checkpoint genes themselves. This suggests a positive feedback circuit that may increase the cell's ability to respond to DNA damage. We make two primary conclusions from these studies. First, MEC1 appears to be the key regulator because it is required for all responses (both transcriptional and cell cycle arrest), while other genes serve only a subset of these responses. Second, the two types of responses, transcriptional induction and cell cycle arrest, appear distinct because both require MEC1 yet only cell cycle arrest requires RAD9. These and other results were used to formulate a working model of checkpoint gene function that accounts for roles of different checkpoint genes in different responses and after different types of damage. The conclusion that the yeast MEC1 gene is a key regulator also has implications for the role of a putative human homologue, the ATM gene.
authors: Molecular and Cellular Biology Department, University of Arizona, Tucson 85721, USA.
authors: G L
authors: GL
authors: Kiser
authors: T A
authors: TA
authors: Weinert
mesh_terms: D017489:CDC28 Protein Kinase, S cerevisiae / Q000502:physiology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005246:Feedback; D005656:Fungal Proteins / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005800:Genes, Fungal; D018816:Genes, cdc / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D047908:Intracellular Signaling Peptides and Proteins; D008957:Models, Genetic; D009687:Nuclear Proteins; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D014158:Transcription, Genetic; D015003:Yeasts / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C501395:RAD17 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; C067022:RAD53 protein, S cerevisiae