Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis

• Published in: Cell reports (Cambridge) Vol. 42; no. 7; p. 112768
• Main Authors: Armstrong, Claire, Passanisi, Victor J., Ashraf, Humza M., Spencer, Sabrina L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2023; Elsevier
• Subjects: 3′hExo; CDK2; Cell Cycle; Cell Cycle Proteins - metabolism; CP: Cell biology; CP: Molecular biology; Cyclin E - genetics; Cyclin E - metabolism; Cyclin-Dependent Kinase 2 - metabolism; Feedback; FLASH; histone locus body; Histones - metabolism; Lsm11; NASP; NPAT; Nuclear Proteins - metabolism; replication-dependent histone; restriction point; RNA, Messenger; S Phase; SLBP; NPAT; SLBP; Lsm11; NASP; CP: Cell biology; restriction point; CDK2; CP: Molecular biology; replication-dependent histone; histone locus body; 3′hExo; FLASH
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112768

Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this burst in histone biosynthesis as DNA replication begins. Here, we use single-cell time-lapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the restriction point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert. [Display omitted] •Histone locus body (HLB) formation is driven by E2F-mediated expression of NPAT and FLASH•Histone transcription is triggered by cyclin E-CDK2’s phosphorylation of NPAT•HLB formation and activation of histone transcription are decouplable•DNA replication regulates histone mRNA degradation via soluble histone levels Histone biosynthesis is coordinated with DNA replication. Synthesis begins at the restriction point and is followed by a burst at the G1/S transition. Armstrong et al. show that CDK2-triggered transcription of histone genes and histone mRNA degradation mediated by unincorporated histones act in tandem to regulate histone levels.