The single-strand DNA binding activity of human PC4 prevents mutagenesis and killing by oxidative DNA damage

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Human positive cofactor 4 (PC4) is a transcriptional coactivator with a conserved single-strand DNA (ssDNA) binding domain of unknown function.
• Oxidative stress can lead to DNA mutations, impacting cellular health and potentially causing diseases.

Purpose of the Study:

• To investigate the function of PC4's ssDNA binding domain.
• To determine PC4's role in DNA repair, particularly in response to oxidative damage.
• To explore the interaction between PC4 and DNA repair proteins.

Main Methods:

• Utilized Escherichia coli and Saccharomyces cerevisiae models to study PC4 and its ortholog Sub1.
• Assessed the effect of PC4 on oxidative mutator phenotypes and peroxide sensitivity.
• Investigated the physical interaction between PC4 and human Rad2 homolog XPG using DNA substrates.

Main Results:

• PC4 suppresses the oxidative mutator phenotype in E. coli, requiring its ssDNA binding activity.
• Yeast mutants lacking Sub1 (PC4 ortholog) are sensitive to hydrogen peroxide and exhibit hypermutability.
• PC4 suppresses peroxide sensitivity in yeast, indicating a conserved function.
• PC4 physically interacts with XPG and is recruited to DNA, displacing XPG and forming a PC4-DNA complex.

Conclusions:

• PC4 plays a significant role in protecting against oxidative DNA damage.
• PC4's ssDNA binding activity is crucial for its DNA repair function.
• PC4 may be involved in global or transcription-coupled repair pathways by mediating XPG release from DNA substrates.