Protein hnRNPA1 binds to a critical G-rich element of KRAS and unwinds G-quadruplex structures: implications in transcription.
The promoter of the KRAS proto-oncogene contains a critical nuclease hypersensitive element (NHE) forming G-quadruplex structures that are recognized by nuclear proteins: PARP-1, Ku70 and hnRNPA1. Here we have studied the interaction between hnRNPA1 (and its derivative UP1) and the G-quadruplexes of KRAS by EMSA, FRET and CD experiments. FRET and CD showed that hnRNPA1/UP1 is able to unfold the G-quadruplexes of KRAS and facilitate the quadruplex to duplex transformation. This finding strengthens our previous hypothesis that the transcription regulation of KRAS is mediated by G-quadruplex structures. Against this background we designed G4-decoy oligonucleotides specific for KRAS that exhibit a strong antiproliferative effect in pancreatic cancer cells.
Xodo
Luigi
L
Department of Biomedical Science and Technology, School of Medicine, P.le Kolbe 4, 33100 Udine, Italy. lxodo@makek.dstb.uniud.it
Paramasivam
Manikandan
M
Membrino
Alexandro
A
Cogoi
Susanna
S
D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D011905:Genes, ras; D006147:Guanine / Q000032:analysis; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014158:Transcription, Genetic; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D006147:Guanine; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins