Abstract
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM.
Highlights
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance
APEX1 and APEX2 are overexpressed in MM In our previous study, evaluation of gene expression by microarray indicated that expression of APEX1 and/or APEX2 in MM cell lines and a subset of MM patient samples was upregulated relative to normal plasma cell samples[23]
To further investigate AP nucleases in MM, here we evaluated their expression at protein level using immunocytochemistry and western blotting and confirmed upregulation in MM relative to normal plasma cells (Fig. 1a, b)
Summary
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We show that APEX1 and APEX2, major BER proteins, contribute to regulation of HR in MM These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM. Multiple DNA for growth, survival, and progression of disease, and repair mechanisms exist and ensure that these alterations are constantly and efficiently repaired in normal cells. Consistent with this, we have previously demonstrated that elevated HR mediates genomic instability and progression in MM23 Using another cancer model system (Barrett’s adenocarcinoma), we demonstrated that dysregulated HR disrupts genomic integrity[24] and stability[25], and transgenic as well as chemical suppression of HR, significantly reduced both the genomic instability as well as growth of cancer cells in mice[26]. Identification of mechanisms underlying dysregulation of HR may help prevent genomic evolution and provide novel targets for cancer prevention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
