KG-driven RNA polymerase II transcription of cyclin D1 licenses malic enzyme 2 to promote cell-cycle progression

Increased metabolic activity usually provides energy and nutrients for biomass synthesis and is indispens-able for the progression of the cell cycle. Here, we find a role for a-ketoglutarate (aKG) generation in regu-lating cell-cycle gene transcription. A reduction in cellular aKG levels triggered by malic enzyme 2 (ME2) or isocitrate dehydrogenase 1 (IDH1) depletion leads to a pronounced arrest in G1 phase, while aKG supple-mentation promotes cell-cycle progression. Mechanistically, aKG directly binds to RNA polymerase II (RNAPII) and increases the level of RNAPII binding to the cyclin D1 gene promoter via promoting pre-initiation complex (PIC) assembly, consequently enhancing cyclin D1 transcription. Notably, aKG addition is sufficient to restore cyclin D1 expression in ME2-or IDH1-depleted cells, facilitating cell-cycle progression and prolif-eration in these cells. Therefore, our findings indicate a function of aKG in gene transcriptional regulation and cell-cycle control.