Msa1 and Msa2 Modulate G1-Specific Transcription to Promote G1 Arrest and the Transition to Quiescence in Budding Yeast

摘要

Yeast that naturally exhaust their glucose source can enter a quiescent state that is characterized by reduced cell size, and high cell density, stress tolerance and longevity. The transition to quiescence involves highly asymmetric cell divisions, dramatic reprogramming of transcription and global changes in chromatin structure and chromosome topology. Cells enter quiescence from G1 and we find that there is a positive correlation between the length of G1 and the yield of quiescent cells. The Swi4 and Swi6 transcription factors, which form the SBF transcription complex and promote the G1 to S transition in cycling cells, are also critical for the transition to quiescence. Swi6 forms a second complex with Mbp1 (MBF), which is not required for quiescence. These are the functional analogues of the E2F complexes of higher eukaryotes. Loss of the RB analogue, Whi5, and the related protein Srl3/Whi7, delays G1 arrest, but it also delays recovery from quiescence. Two M BF- and S BF- A ssociated proteins have been identified that have little effect on SBF or MBF activity in cycling cells. We show that these two related proteins, Msa1 and Msa2, are specifically required for the transition to quiescence. Like the E2F complexes that are quiescence-specific, Msa1 and Msa2 are required to repress the transcription of many SBF target genes, including SWI4 , the CLN2 cyclin and histones, specifically after glucose is exhausted from the media. They also activate transcription of many MBF target genes. msa1msa2 cells fail to G1 arrest and rapidly lose viability upon glucose exhaustion. msa1msa2 mutants that survive this transition are very large, but they attain the same thermo-tolerance and longevity of wild type quiescent cells. This indicates that Msa1 and Msa2 are required for successful transition to quiescence, but not for the maintenance of that state. Author Summary In spite of the many differences between yeast and humans, the basic strategies that regulate the cell division cycle are fundamentally conserved. In this study, we extend these parallels to include a common strategy by which cells transition from proliferation to quiescence. The decision to divide is made in the G1 phase of the cell cycle. During G1, the genes that drive DNA replication are repressed by the E2F/RB complex. When a signal to divide is received, RB is removed and the complex is activated. When cells commit to a long term, but reversible G1 arrest, or quiescence, they express a novel E2F/RB-like complex, which promotes and maintains a stable repressive state. Yeast cells contain a functional analog of E2F/RB, called SBF/Whi5, which is activated by a similar mechanism in proliferating yeast cells. In this study, we identify two novel components of the SBF/Whi5 complex whose activity is specific to the transition to quiescence. These factors, Msa1 and Msa2, repress SBF targets and are required for the long term, but reversible G1 arrest that is critical for achieving a quiescent state.