Amazing stuff!
"When a cell gets ready to divide, it shuts down its gene-reading machinery almost entirely. ...
For decades, the mechanism behind that shutdown was only partially understood. A new study ... identifies a missing piece: an enzyme best known for tagging RNA molecules that turns out to be wired into the cell division machinery itself. The findings ... may point toward new cancer therapies. ...
The new paper shows this same chain reaction [as in RNA transcription] is triggered the moment a cell commits to division. An enzyme called CDK1 activates METTL3, which sets off the same cascade of events. However, in this case, the goal is to complete transcription and clear mRNA molecules from DNA, rather than making new proteins. ...
The window for all of this is narrow. "Mitosis only lasts about an hour," ... Cells have to condense their chromosomes, segregate them, and complete the whole process within a short period of time. “So it has to be very tightly controlled and very quick [???]." ..."
From the highlights and abstract:
"Highlights
• CDK1 phosphorylates the m6A methyltransferase METTL3 at Ser43 upon mitotic entry
• METTL3 phosphorylation allows 7SK methylation and P-TEFb release for transcription
• METTL3 phosphorylation is required for timely mitotic exit and chromosome segregation
• CDK1-METTL3-7SK-P-TEFb axis integrates RNA methylation into mitotic progression
Summary
Transcriptional elongation undergoes extensive remodeling at mitotic entry, yet how elongation control is integrated into core cell-cycle kinase networks remains unclear.
Here, we identify the m6A methyltransferase METTL3 as a direct substrate of the mitotic kinase CDK1 in mammalian cells.
CDK1-dependent phosphorylation of METTL3 at Ser43 is sharply induced at mitotic entry and promotes m6A methylation of the noncoding RNA 7SK, resulting in release of positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP) complex.
This activation of the m6A/7SK/P-TEFb axis facilitates genome-wide clearance of RNA polymerase II and supports timely mitotic progression.
Endogenous mutation of METTL3 Ser43 or disruption of 7SK methylation impairs elongation dynamics, delays mitotic exit, and increases chromosome missegregation.
These findings integrate RNA methylation into the CDK1-driven mitotic program and reveal a mechanism by which transcriptional elongation is coordinated with chromosome segregation fidelity."
Graphical abstract
Figure 1 METTL3 is required for cell-cycle progression and is phosphorylated at mitosis
Figure 4 The METTL3/7SK/HEXIM1/P-TEFb axis regulates cell-cycle progression
No comments:
Post a Comment