Regulation of the G1-to-S transition
Inactivation of the Retinoblastoma protein (pRB) leads to unregulated cell cycle progression promoting uncontrolled cell growth, genomic instability and aneuploidy, hallmarks of tumor progression. pRB tumor suppressor activity is achieved through binding and regulating the E2F family of transcription factors. Even though many individual regulators of the pRB-E2F complex are known, an integrative view of all the regulatory events controlling the G1/S transition is required to anticipate putative interventions able to block proliferative processes. Fission yeast is an ideal system to investigate fundamental mechanisms that control cell cycle progression.We are characterizing the regulation of the yeast MBF complex (functional homolog of pRB/E2F).Like its mammalian counterpart, the regulated activity of this complex is essential for the G1-to-S transition.We have shown how MBF is regulated under replication stress, but how MBF is regulated in an unperturbed cell cycle is still not well known.To elucidate this, we have done a double genomic screen searching for global regulators of MBF using a reporter strain that allows the measurement of MBF activity in live cells (either by FACS or microscope). Among several regulators, we have found that the HAT Gcn5 and other chromatin remodelers play an essential role in the regulation of the G1/S transcriptional wave.
Ayté, J. et al. (2001) Feedback regulation of the MBF transcription factor by ciclin Cig2. Nature Cell Biol. 3:1043-1050.
Gómez-Escoda, B. et al. (2011) Yox1 links MBF-dependent transcription to completion of DNA synthesis. EMBO Reports 12:84-89.
Ivanova, T. et al. (2013) The DNA damage and the DNA replication checkpoints converge at the MBF transcription factor. Mol. Biol. Cell 24:3350-3357.
Gaspa, L. et al. (2016) A functional genome-wide genetic screening identifies new pathways controlling the G1/S transcriptional wave. Cell Cycle 15:720-72.
González-Medina, A. et al. (2019) Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave. Nucleic Acids Res. 47:8439-8451.