The human AP-endonuclease 1 (APE1) is a DNA G-quadruplex structure binding protein and regulates KRAS expression in pancreatic ductal adenocarcinoma cells

Abstract Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive types of cancer, is characterized by aberrant activity of oncogenic KRAS. A nuclease-hypersensitive GC-rich region in KRAS promoter can fold into a four-stranded DNA secondary structure called G-quadruplex (G4), known to re...

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Published in:Nucleic acids research 2022-04, Vol.50 (6), p.3394-3412
Main Authors: Pramanik, Suravi, Chen, Yingling, Song, Heyu, Khutsishvili, Irine, Marky, Luis A, Ray, Sutapa, Natarajan, Amarnath, Singh, Pankaj K, Bhakat, Kishor K
Format: Article
Language:English
Subjects:
Carcinoma, Pancreatic Ductal - genetics
DNA - chemistry
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
Endonucleases - metabolism
G-Quadruplexes
Gene regulation, Chromatin and Epigenetics
Humans
Pancreatic Neoplasms
Pancreatic Neoplasms - metabolism
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
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Summary:Abstract Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive types of cancer, is characterized by aberrant activity of oncogenic KRAS. A nuclease-hypersensitive GC-rich region in KRAS promoter can fold into a four-stranded DNA secondary structure called G-quadruplex (G4), known to regulate KRAS expression. However, the factors that regulate stable G4 formation in the genome and KRAS expression in PDAC are largely unknown. Here, we show that APE1 (apurinic/apyrimidinic endonuclease 1), a multifunctional DNA repair enzyme, is a G4-binding protein, and loss of APE1 abrogates the formation of stable G4 structures in cells. Recombinant APE1 binds to KRAS promoter G4 structure with high affinity and promotes G4 folding in vitro. Knockdown of APE1 reduces MAZ transcription factor loading onto the KRAS promoter, thus reducing KRAS expression in PDAC cells. Moreover, downregulation of APE1 sensitizes PDAC cells to chemotherapeutic drugs in vitro and in vivo. We also demonstrate that PDAC patients’ tissue samples have elevated levels of both APE1 and G4 DNA. Our findings unravel a critical role of APE1 in regulating stable G4 formation and KRAS expression in PDAC and highlight G4 structures as genomic features with potential application as a novel prognostic marker and therapeutic target in PDAC.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkac172