ERCC1 abundance is an indicator of DNA repair-apoptosis decision upon DNA damage

Abstract

AbstractDNA repair is essential for successful propagation of genetic material and fidelity of transcription. Nucleotide excision repair (NER) is one of the earliest DNA repair mechanisms, functionally conserved from bacteria to human. The fact that number of NER genes vary significantly between prokaryotes and metazoans gives the insight that NER proteins have evolved to acquire additional functions to combat challenges associated with a diploid genome, including being involved in the decision between DNA repair and apoptosis. However, no direct association between apoptosis and NER proteins has been shown to date. In this study, we induced apoptosis with a variety of agents, including oxaliplatin, doxorubicin and TRAIL, and observed changes in the abundance and molecular weight of NER complex proteins. Our results showed that XPA, XPC and ERCC1 protein levels change during DNA damage-induced apoptosis. Among these, ERCC1 decrease was observed as a pre-mitochondria depolarisation event which marks the “point of no return” in apoptosis signalling. ERCC1 decrease was due to proteasomal degradation upon lethal doses of oxaliplatin exposure. When ERCC1 protein was stabilised using proteasome inhibitors, the pro-apoptotic activity of oxaliplatin was attenuated. These results explain why clinical trials using proteasome inhibitors and platinum derivatives showed limited efficacy in carcinoma treatment and also the importance of how deep understanding of DNA repair mechanisms can improve cancer therapy.