Elevated PAF1-RAD52 axis confers chemoresistance to human cancers

Sanchita Rauth; Koelina Ganguly; Pranita Atri; Seema Parte; Rama Krishna Nimmakayala; Venkatesh Varadharaj; Palanisamy Nallasamy; Raghupathy Vengoji; Ayoola O Ogunleye; Imayavaramban Lakshmanan; Ramakanth Chirravuri; Mika Bessho; Jesse L Cox; Jason M Foster; Geoffrey A Talmon; Tadayoshi Bessho; Apar Kishor Ganti; Surinder K Batra; Moorthy P Ponnusamy

doi:10.1016/j.celrep.2023.112043

Elevated PAF1-RAD52 axis confers chemoresistance to human cancers

Cell Rep. 2023 Feb 28;42(2):112043. doi: 10.1016/j.celrep.2023.112043. Epub 2023 Jan 28.

Authors

Sanchita Rauth¹, Koelina Ganguly¹, Pranita Atri¹, Seema Parte¹, Rama Krishna Nimmakayala¹, Venkatesh Varadharaj¹, Palanisamy Nallasamy¹, Raghupathy Vengoji¹, Ayoola O Ogunleye¹, Imayavaramban Lakshmanan¹, Ramakanth Chirravuri¹, Mika Bessho², Jesse L Cox³, Jason M Foster⁴, Geoffrey A Talmon³, Tadayoshi Bessho², Apar Kishor Ganti⁵, Surinder K Batra⁶, Moorthy P Ponnusamy⁷

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
² Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
³ Department of Pathology and Microbiology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
⁴ Department of Surgery, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Division of Oncology-Hematology, Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
⁶ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA. Electronic address: sbatra@unmc.edu.
⁷ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, NE, USA. Electronic address: mpalanim@unmc.edu.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Carcinoma, Non-Small-Cell Lung* / genetics
Cell Line, Tumor
Cisplatin / therapeutic use
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Drug Resistance, Neoplasm*
Gemcitabine / therapeutic use
Humans
Lung Neoplasms* / genetics
Rad52 DNA Repair and Recombination Protein
Transcription Factors

Substances

Cisplatin
Deoxycytidine
Gemcitabine
PAF1 protein, human
Rad52 DNA Repair and Recombination Protein
RAD52 protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding