XPC deficiency is related to APE1 and OGG1 expression and function
Julliane Tamara Araújo de Melo1, Ana Rafaela de Souza Timoteo1, Tirzah Braz Petta Lajus1
1Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
Abstract:
Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.
Insights
XPC deficiency, linked to nucleotide excision repair (NER), impacts oxidative DNA damage response. XPC protein may regulate base excision repair (BER) enzymes, suggesting new roles beyond NER.
Area of Science:
- Molecular Biology
- Genetics
- DNA Repair Mechanisms
Background:
- Oxidative DNA damage contributes to neurodegeneration and tumors in nucleotide excision repair (NER) deficiency syndromes like Xeroderma Pigmentosum (XP).
- NER's role in removing oxidized DNA damage and potential interactions with base excision repair (BER) enzymes are increasingly recognized.
Purpose of the Study:
- To investigate the expression, localization, and activity of APE1 and OGG1 DNA repair enzymes under oxidative stress in XPC-deficient cells.
- To elucidate the role of XPC protein in regulating BER enzymes and cellular response to oxidative stress.
Main Methods:
- Analysis of APE1 and OGG1 mRNA levels in XPC-deficient and complemented fibroblasts.
- Assessment of cellular sensitivity to oxidative stress.
- Measurement of OGG1 and APE1 enzyme activity.
- Co-immunoprecipitation to detect protein-protein interactions between XPC and APE1.
Main Results:
- XPC-deficient cells showed lower endogenous APE1 and OGG1 mRNA levels but no hypersensitivity to oxidative stress.
- Partial and transient XPC complementation in cells increased OGG1 expression and activity, but not APE1.
- A physical interaction was observed between XPC and APE1 proteins.
Conclusions:
- XPC deficiency impacts oxidative DNA damage response partly through altered BER enzyme regulation, not solely via NER deficiency.
- XPC protein may have novel functions in regulating BER pathway components, including interactions with APE1.
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