Open AccessRNA polymerase II trapped on a molecular treadmill: Structural basis of persistent transcriptional arrest by a minor groove DNA binder
Author(s) -
Juntaek Oh,
Tiezheng Jia,
Jun Xu,
Jenny Chong,
Peter B. Dervan,
Dong Wang
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114065119
Subject(s) - processivity , rna polymerase ii , dna , rna polymerase iii , transcription (linguistics) , transcriptional regulation , biology , rna , polymerase , rna polymerase , microbiology and biotechnology , chemistry , biochemistry , rna dependent rna polymerase , transcription factor , gene , gene expression , promoter , linguistics , philosophy
Significance Hairpin pyrrole-imidazole (Py-Im) polyamides can be programmed to bind a broad repertoire of DNA sequences. Py-Im small molecules can be used to target cancer-specific coding regions and block transcription elongation. This transcription blockage by Py-Im cannot be rescued by transcription elongation factors, such as TFIIS. The mechanism by which Py-Im blocks transcription remains elusive. To understand the structural basis of this strong transcription blockage, we solved five different structures containing an eight-ring hairpin Py-Im bound with either a Pol II elongation complex (EC) or a DNA duplex. These structures revealed that Py-Im can trap Pol II EC in a treadmill-like manner. This knowledge may pave the way for the development of small molecules that inhibit transcriptional addiction in cancer.