Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence

Jacob Peter Matson; Amy M. House; Gavin D. Grant; Huaitong Wu; Joanna Perez; Jeanette Gowen Cook

It is unclear why cells re-entering G0 load MCM slowly since it isn't simply the abundance of Cdc6. The difference may be caused by one or more of the fundamental differences in G1 regulation between cell cycle re-entry and active proliferation. These differences include the status of Rb phosphorylation which is monophosphorylated in proliferating G1 cells, but unphosphorylated in G0 (Narasimha, Kaulich, Shapiro et al., 2014) . Rb-dependent genes include those whose products are directly involved in MCM loading, and these genes are subject to unique transcriptional repression by the DREAM complex in G0 that must be reversed at cell cycle re-entry (Litovchick et al., 2007) . Proliferating cells also load MCM both before and after Rb is removed from chromatin, but cells re-entering G1 from G0 only load MCM after Rb is removed from chromatin (HÃ¥land et al., 2015) . CDK2 is constitutively nuclear in proliferating cells, but is cytoplasmic in G0 (Brown et al., 2004; Dietrich et al., 1997) . Of additional particular relevance is the indication of a kinase-independent function of Cyclin E1 to promote loading that is only required in cells re-entering the cycle form G0 but not in other cell cycles (Geng et al., 2003 (Geng et al., , 2007 . These differences illustrate that cell cycle re-entry into G1 from G0 poses additional challenges and requirements not encountered during G1 . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/558783 doi: bioRxiv preprint in actively proliferating cells. It is striking however that both the checkpoint defect and slow MCM loading are normal just one cell cycle later after mitosis.