Active transcriptomic and proteomic reprogramming in the C. elegans nucleotide excision repair mutant xpa-1

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Oxidative DNA damage is linked to aging and stress responses in Nucleotide Excision Repair (NER) deficient models.
• Understanding the molecular mechanisms driving these responses in NER-deficient organisms is crucial.

Purpose of the Study:

• To provide a quantitative proteomic and transcriptomic analysis of the NER-defective xpa-1 mutant in Caenorhabditis elegans.
• To elucidate the upstream requirements and downstream effectors of transcriptomic reprogramming in response to DNA damage.

Main Methods:

• Quantitative proteomics and transcriptomics were employed to compare the xpa-1 mutant with wild-type C. elegans.
• Biochemical assays measured reactive oxygen species (ROS) and Adenosine triphosphate (ATP) levels.
• RNA-interference was used to deplete specific DNA repair enzymes and transcription factors.

Main Results:

• Proteomic and transcriptomic data revealed activation of oxidative stress responses, confirmed by increased ROS and ATP.
• Lesion-detection enzymes NTH-1, XPC-1, and DDB-1 were identified as essential for transcriptomic reprogramming.
• SKN-1 and SLR-2, but not DAF-16, were identified as key transcription factors mediating the reprogramming.

Conclusions:

• Transcriptomic reprogramming in NER-deficient C. elegans is driven by lesion-detection enzymes, not solely by cyclopurine lesion accumulation.
• These enzymes generate a genomic stress signal that leads to widespread gene expression changes.
• The findings offer insights into DNA repair pathways and aging-related stress responses.