@article{b15255e0604a4c33a421562137111ede,
title = "Elevated PAF1-RAD52 axis confers chemoresistance to human cancers",
abstract = "Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers.",
keywords = "CP: Cancer, DNA repair, PAF1, RAD52, chemoresistance, lung cancer, ovarian cancer, pancreatic cancer",
author = "Sanchita Rauth and Koelina Ganguly and Pranita Atri and Seema Parte and Nimmakayala, {Rama Krishna} and Venkatesh Varadharaj and Palanisamy Nallasamy and Raghupathy Vengoji and Ogunleye, {Ayoola O.} and Imayavaramban Lakshmanan and Ramakanth Chirravuri and Mika Bessho and Cox, {Jesse L.} and Foster, {Jason M.} and Talmon, {Geoffrey A.} and Tadayoshi Bessho and Ganti, {Apar Kishor} and Batra, {Surinder K.} and Ponnusamy, {Moorthy P.}",
note = "Funding Information: We very much appreciate the kind technical help of Kavita Mallya. We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center for helping with confocal microscopy. The graphical abstract was created using BioRender.com. The authors were supported by grants from the National Institutes of Health (R01 CA273349, R01 CA263575, R01 CA256973, R01 CA206444, R01 CA210637, R01 CA228524, U01 CA200466, U01 CA210240, and P01 CA217798) and Nebraska Department of Health and Human Services Stem Cell Grant LB606/2022-10. S.R. contributed to designing the project and performed most of the work. K.G. contributed to Figures 2 and 5, through ChIP assay and tumor implantation. P.A. and R.C. contributed to statistical and bioinformatics analysis. S.P. R.K.N. V.V. P.N. A.O.O. and I.L. assisted with some of the work. R.V. contributed to Figure 4 through comet assay and data analysis. M.B. and T.B. have supervised the analysis related to DNA-repair assays. J.L.C. and G.A.T. have performed the pathological analysis and scoring. J.M.F. has provided the fresh tissue samples for organoid generation. A.K.G. has helped with the lung-cancer-related studies. S.K.B. and M.P.P. have supervised and reviewed the manuscript. S.K.B. is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no competing interests. Funding Information: We very much appreciate the kind technical help of Kavita Mallya. We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center for helping with confocal microscopy. The graphical abstract was created using BioRender.com . The authors were supported by grants from the National Institutes of Health ( R01 CA273349 , R01 CA263575 , R01 CA256973 , R01 CA206444 , R01 CA210637 , R01 CA228524 , U01 CA200466 , U01 CA210240 , and P01 CA217798 ) and Nebraska Department of Health and Human Services Stem Cell Grant LB606/2022-10 . Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = feb,
day = "28",
doi = "10.1016/j.celrep.2023.112043",
language = "English (US)",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}