Apoptosis Triggers Specific, Rapid, and Global mRNA Decay with 3' Uridylated Intermediates Degraded by DIS3L2

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Apoptosis involves cellular damage, but the fate of RNA during this process is largely unknown.
• Previous research has focused on DNA, protein, and lipid damage during apoptosis.

Purpose of the Study:

• To investigate the degradation of RNA during apoptosis.
• To identify the mechanisms and key players involved in RNA decay during programmed cell death.

Main Methods:

• Analysis of mRNA and noncoding RNA degradation during apoptosis.
• Investigating the role of mitochondrial outer membrane permeabilization and caspase activation.
• Identifying enzymes involved in RNA tailing (terminal uridylyl transferases - TUTases) and degradation (exonucleases).
• Utilizing knockdown and overexpression of key enzymes (DIS3L2, ZCCHC6, ZCCHC11) to assess their impact.

Main Results:

• Messenger RNAs (mRNAs) are rapidly and globally degraded during apoptosis, unlike noncoding RNAs.
• Apoptotic mRNA decay is an early event, preceding DNA fragmentation and translation initiation factor changes.
• The process depends on mitochondrial outer membrane permeabilization and caspase activation.
• Specific enzymes, terminal uridylyl transferases (TUTases) ZCCHC6 and ZCCHC11, add uridylate tails to mRNA fragments, which are then degraded by the exonuclease DIS3L2.
• Inhibition of TUTases or DIS3L2, or overexpression of DIS3L2, significantly impacts mRNA decay, translation arrest, and cell death.

Conclusions:

• Global mRNA decay is a significant and previously overlooked hallmark of apoptosis.
• The TUTase-DIS3L2 pathway is crucial for executing apoptotic mRNA decay and subsequent cell death.
• Targeting this pathway could offer new strategies for modulating apoptosis.