A two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways

Area of Science:

• Molecular Biology
• Genetics
• Aging Research

Background:

• Nucleotide Excision Repair (NER) deficiency causes premature aging with oxidative stress and altered insulin-like signaling (ILS).
• The specific DNA lesions driving these aging phenotypes in NER-deficient models remain unidentified.
• Base Excision Repair (BER) enzymes, like NTH-1, initiate repair of oxidative DNA damage.

Purpose of the Study:

• To investigate the role of Base Excision Repair (BER) in generating DNA damage that contributes to aging phenotypes in Nucleotide Excision Repair (NER) deficient mutants.
• To identify the specific DNA lesions responsible for accelerated aging in NER-deficient organisms.

Main Methods:

• Utilized Caenorhabditis elegans models with mutations in NER (xpa-1) and BER (nth-1) genes.
• Performed lifespan assays, oxidative stress response analysis, and global gene expression profiling (transcriptomics).

Main Results:

• Loss of NTH-1 (a BER enzyme) restored normal lifespan and abolished oxidative stress responses in xpa-1 (NER-deficient) mutants.
• NTH-1 deficiency induced oxidative stress and altered gene expression, including upregulation of stress response genes and downregulation of ILS.
• Combined loss of NTH-1 and XPA-1 resulted in distinct transcriptomic changes, including downregulation of cell cycle and DNA repair pathways.

Conclusions:

• BER pathway activity contributes to the generation of transcription-blocking DNA lesions from oxidative damage, particularly in the context of NER deficiency.
• The study suggests that DNA lesions relevant to aging are repair intermediates arising from attempted or aberrant BER processing of lesions normally handled by NER.
• Targeting BER may offer a therapeutic strategy to mitigate aging phenotypes associated with unrepaired DNA damage.