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

Yanting Yang 1, Zhenxi Zhang 1, Wei Li 1, Yufan Si 1, Li Li 1, Wenjing Du 2

Cell Rep. 2023 Jul 7;42(7):112770. doi: 10.1016/j.celrep.2023.112770.

PMID: 37422761

Abstract

Increased metabolic activity usually provides energy and nutrients for biomass synthesis and is indispensable for the progression of the cell cycle. Here, we find a role for α-ketoglutarate (αKG) generation in regulating cell-cycle gene transcription. A reduction in cellular αKG levels triggered by malic enzyme 2 (ME2) or isocitrate dehydrogenase 1 (IDH1) depletion leads to a pronounced arrest in G1 phase, while αKG supplementation promotes cell-cycle progression. Mechanistically, αKG 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, αKG addition is sufficient to restore cyclin D1 expression in ME2- or IDH1-depleted cells, facilitating cell-cycle progression and proliferation in these cells. Therefore, our findings indicate a function of αKG in gene transcriptional regulation and cell-cycle control.