Loading...
Identification of evolutionarily conserved DNA damage response genes that alter sensitivity to cisplatin
Gaponova, Anna V. Deneka, Alexander Y. Beck, Tim N. Andrianov, Gregory Nikonova, Anna S. Nicolas, Emmanuelle Einarson, Margret B. Serebriiskii, Ilya G.
Gaponova, Anna V.
Deneka, Alexander Y.
Beck, Tim N.
Andrianov, Gregory
Nikonova, Anna S.
Nicolas, Emmanuelle
Einarson, Margret B.
Serebriiskii, Ilya G.
Citations
Altmetric:
Genre
Journal article
Date
2016-11-15
Advisor
Committee member
Department
Cancer and Cellular Biology
Permanent link to this record
Collections
Research Projects
Organizational Units
Journal Issue
DOI
http://dx.doi.org/10.18632/oncotarget.13353
Abstract
Ovarian, head and neck, and other cancers are commonly treated with cisplatin and other DNA damaging cytotoxic agents. Altered DNA damage response (DDR) contributes to resistance of these tumors to chemotherapies, some targeted therapies, and radiation. DDR involves multiple protein complexes and signaling pathways, some of which are evolutionarily ancient and involve protein orthologs conserved from yeast to humans. To identify new regulators of cisplatin-resistance in human tumors, we integrated high throughput and curated datasets describing yeast genes that regulate sensitivity to cisplatin and/or ionizing radiation. Next, we clustered highly validated genes based on chemogenomic profiling, and then mapped orthologs of these genes in expanded genomic networks for multiple metazoans, including humans. This approach identified an enriched candidate set of genes involved in the regulation of resistance to radiation and/or cisplatin in humans. Direct functional assessment of selected candidate genes using RNA interference confirmed their activity in influencing cisplatin resistance, degree of γH2AX focus formation and ATR phosphorylation, in ovarian and head and neck cancer cell lines, suggesting impaired DDR signaling as the driving mechanism. This work enlarges the set of genes that may contribute to chemotherapy resistance and provides a new contextual resource for interpreting next generation sequencing (NGS) genomic profiling of tumors.
Description
Citation
Gaponova AV, Deneka AY, Beck TN, Liu H, Andrianov G, Nikonova AS, et al. Identification of evolutionarily conserved DNA damage response genes that alter sensitivity to cisplatin. Oncotarget. 2016 Nov 15;8:19156-19171. doi:10.18632/oncotarget.13353.
Citation to related work
Impact Journals
Has part
Oncotarget, Vol. 8
ADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu