rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription.

Area of Science:

• Molecular Biology
• Immunology
• Genetics

Background:

• Chemo- and radio- therapies damage DNA, impacting ribosomal RNA (rRNA) transcription and processing.
• The biological outcomes of these rRNA processing disruptions are not fully understood.

Purpose of the Study:

• To investigate the consequences of DNA damage on rRNA transcription and processing.
• To elucidate the mechanism by which aberrant rRNA species activate immune signaling pathways.

Main Methods:

• Analysis of aberrant rRNA transcripts generated from DNA breaks.
• Investigating the engagement of double-stranded RNA pattern recognition receptors (MDA5 and RIG-I).
• Purification of endogenous MDA5-filaments and sequencing.

Main Results:

• DNA damage leads to truncated sense-antisense rRNA transcripts instead of full-length rRNA.
• These aberrant rRNA transcripts activate immune signaling via MDA5 and RIG-I.
• ATM and ATR kinase activities regulate the accumulation of these truncated rRNA species.

Conclusions:

• Aberrant rRNA transcripts serve as endogenous ligands that activate dsRNA pattern recognition receptors following DNA damage.
• A novel mechanism links nucleolar stress, induced by DNA damage, to the activation of innate immune signaling.