Low extracellular pH inhibits nucleotide excision repair

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Nucleotide excision repair (NER) corrects bulky DNA damage, and its dysfunction is linked to cancer and neurological disorders.
• External factors like oxidative stress and chemicals can impair NER, alongside genetic defects.

Purpose of the Study:

• To investigate the impact of extracellular pH on the efficiency of the NER pathway.
• To understand how varying pH levels affect DNA repair mechanisms and associated proteins.

Main Methods:

• Human keratinocytes (HaCaT) were incubated in media with different pH values (8.4, 7.6, 6.6, 6.2).
• UV-induced DNA damage (pyrimidine dimers: 6-4PPs and CPDs) was assessed.
• The accumulation and release of NER proteins TFIIH and XPG were monitored post-UVC irradiation.
• DNA synthesis rates at repair sites were measured.

Main Results:

• Marked cell death occurred at pH 6.2, with notable inhibition of NER at pH 6.6 and 6.2.
• TFIIH and XPG protein release from damaged DNA sites were delayed or suppressed at lower pH levels.
• DNA synthesis essential for repair was significantly delayed under acidic conditions.

Conclusions:

• Extracellular acidity demonstrably inhibits the nucleotide excision repair pathway.
• This pH-dependent inhibition may contribute to carcinogenesis in chronically inflamed tissues, which are often acidic.