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

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112770-112770, Article 112770
• Main Authors: Yang, Yanting, Zhang, Zhenxi, Li, Wei, Si, Yufan, Li, Li, Du, Wenjing
• Format: Article
• Language: English
• Subjects: Cell Cycle; CP: Molecular biology; cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; G1 Phase; Ketoglutaric Acids - metabolism; malic enzyme 2; RNA Polymerase II; α-ketoglutarate
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112770

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. [Display omitted] •Cyclin D1 is critical for ME2-mediated cell-cycle progression and proliferation•ME2 promotes RNAPII-mediated cyclin D1 transcription via αKG•αKG promotes RNAPII transcription by forming a complex with RPB1 and TFIIS•αKG restores G1-to-S transition and cell division in ME2-depleted cells Yang et al. find a role for ME2 in modulating cell-cycle control via promoting generation of αKG. αKG 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.