TY - JOUR
T1 - SUMO Modification of PAF1/PD2 Enables PML Interaction and Promotes Radiation Resistance in Pancreatic Ductal Adenocarcinoma
AU - Rauth, Sanchita
AU - Karmakar, Saswati
AU - Shah, Ashu
AU - Seshacharyulu, Parthasarathy
AU - Nimmakayala, Rama Krishna
AU - Ganguly, Koelina
AU - Bhatia, Rakesh
AU - Muniyan, Sakthivel
AU - Kumar, Sushil
AU - Dutta, Samikshan
AU - Lin, Chi
AU - Datta, Kaustubh
AU - Batra, Surinder K.
AU - Ponnusamy, Moorthy P.
N1 - Funding Information:
We were supported primarily by the following grants from the National Institutes of Health (P01 CA217798, R01 CA210637, R01 CA183459, R01 CA195586, R01 CA201444, R01 CA228524, F99 CA234962, U01 CA200466, and U01 CA210240) and by the Nebraska Department of Health and Human Services LB595.
Publisher Copyright:
© 2021 American Society for Microbiology. All rights reserved.
PY - 2021/11
Y1 - 2021/11
N2 - RNA polymerase II-associated factor 1 (PAF1)/pancreatic differentiation 2 (PD2) is a core subunit of the human PAF1 complex (PAF1C) that regulates the RNA polymerase II function during transcriptional elongation. PAF1/PD2 has also been linked to the oncogenesis of pancreatic ductal adenocarcinoma (PDAC). Here, we report that PAF1/PD2 undergoes posttranslational modification (PTM) through SUMOylation, enhancing the radiation resistance of PDAC cells. We identified that PAF1/PD2 is preferentially modified by small ubiquitin-related modifier 1 (SUMO 1), and mutating the residues (K)-150 and 154 by site-directed mutagenesis reduces the SUMOylation. Interestingly, PAF1/PD2 was found to directly interact with the promyelocytic leukemia (PML) protein in response to radiation, and inhibition of PAF1/PD2 SUMOylation at K-150/154 affects its interaction with PML. Our results demonstrate that SUMOylation of PAF1/PD2 increased in the radiated pancreatic cancer cells. Furthermore, inhibition of SUMOylation or PML reduces the cell growth and proliferation of PDAC cells after radiation treatment. These results suggest that SUMOylation of PAF1/PD2 interacts with PTM for PDAC cell survival. Furthermore, abolishing the SUMOylation in PDAC cells enhances the effectiveness of radiotherapy. Overall, our results demonstrate a novel PTM and PAF1/PD2 interaction through SUMOylation, and inhibiting the SUMOylation of PAF1/PD2 enhance the therapeutic efficacy for PDAC.
AB - RNA polymerase II-associated factor 1 (PAF1)/pancreatic differentiation 2 (PD2) is a core subunit of the human PAF1 complex (PAF1C) that regulates the RNA polymerase II function during transcriptional elongation. PAF1/PD2 has also been linked to the oncogenesis of pancreatic ductal adenocarcinoma (PDAC). Here, we report that PAF1/PD2 undergoes posttranslational modification (PTM) through SUMOylation, enhancing the radiation resistance of PDAC cells. We identified that PAF1/PD2 is preferentially modified by small ubiquitin-related modifier 1 (SUMO 1), and mutating the residues (K)-150 and 154 by site-directed mutagenesis reduces the SUMOylation. Interestingly, PAF1/PD2 was found to directly interact with the promyelocytic leukemia (PML) protein in response to radiation, and inhibition of PAF1/PD2 SUMOylation at K-150/154 affects its interaction with PML. Our results demonstrate that SUMOylation of PAF1/PD2 increased in the radiated pancreatic cancer cells. Furthermore, inhibition of SUMOylation or PML reduces the cell growth and proliferation of PDAC cells after radiation treatment. These results suggest that SUMOylation of PAF1/PD2 interacts with PTM for PDAC cell survival. Furthermore, abolishing the SUMOylation in PDAC cells enhances the effectiveness of radiotherapy. Overall, our results demonstrate a novel PTM and PAF1/PD2 interaction through SUMOylation, and inhibiting the SUMOylation of PAF1/PD2 enhance the therapeutic efficacy for PDAC.
KW - PAF1
KW - Pancreatic cancer
KW - Polymorphonuclear leukocytes
KW - Radiation resistance
KW - SUMO1
KW - Sumoylation
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U2 - 10.1128/MCB.00135-21
DO - 10.1128/MCB.00135-21
M3 - Article
C2 - 34570619
AN - SCOPUS:85120055769
VL - 41
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 12
M1 - e00135-21
ER -