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Detailing the SAGA pathway

Our initial efforts defining elements in the SAGA pathway during CDK4/6 inhibition in cancer cells defined the necessity of MDM2 down-regulation, ATRX relocalization, and suppression of HRAS in a variety of cancer cell types. While MDM2 down-regulation and suppression of HRAS transcription are specific for CDK4/6 therapy induced senescence, ATRX relocalization is well conserved and is seen during other types of cellular senescence as well, both in primary cells such as oncogene induced senescence, DNA damage induced senescence, and replicative senescence, and in cancer cells treated with DNA damaging agents. Our interest in understanding the CDK4/6 inhibition mechanisms is related to the clinical applications and is discussed below, but on the more basic science side we are interested in understanding how ATRX relocalization occurs as this is an early event in the choice between quiescence and senescence and might impact on understanding how disseminated tumor cells maintain dormancy and how immunologic memory is established.

To identify other elements essential during SAGA, we also developed a cellular system in which cancer cells progress synchronously from quiescence into senescence following CDK4/6 inhibition and have mined this temporally by RNA-seq and metabolic seq (Klein, in preparation). Genes and metabolic pathways that have been uncovered are currently being assessed for their importance to the different phenotypes of senescent cells, i.e. the transition from reversible to irreversible growth arrest and the apoptotic resistance of senescent cells, and being evaluated in other types of cellular senescence. To gain additional insight, not only will we continue to mine the available data, but hope to expand on how we interrogate this system.