Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters

Abstract

G-quadruplex (G4) structures that can form at guanine-rich genomic sites, including telomeres and gene promoters, are actively involved in genome maintenance, replication, and transcription, through finely tuned interactions with protein networks. In the present study, we identified the intermediate filament protein Vimentin as a binder with nanomolar affinity for those G-rich sequences that give rise to at least two adjacent G4 units, named G4 repeats. This interaction is supported by the N-terminal domains of soluble Vimentin tetramers. The selectivity of Vimentin for G4 repeats versus individual G4s provides an unprecedented result. Based on GO enrichment analysis performed on genes having putative G4 repeats within their core promoters, we suggest that Vimentin recruitment at these sites may contribute to the regulation of gene expression during cell development and migration, possibly by reshaping the local higher-order genome topology, as already reported for lamin B.

G-quadruplexes formation within the promoter of TEAD4 oncogene and their interaction with Vimentin

“…In a previous study ( Ceschi et al, 2022 ) the Q-PARSE bioinformatics tool was used to search sequences containing two contiguous G4-forming elements in the region covering 100 nucleotides upstream the transcription starting site of human genes. The search was extended to both, the forward and reverse strands.…”

“…Recently, it has been observed that Vimentin, an intermediate filament (IF) protein, is able to interact selectively with G4-repeats. This complex involves only the tetrameric form of the protein that is found within the nucleus as a soluble nuclear fraction ( Ceschi et al, 2022 ). Although an architectural role has long been considered the main function of Vimentin, it is well recognized that it also participates to various signaling cascades and it can act as a transcriptional regulator within metastatic cancer cells ( Mergui et al, 2010 ), ( Jang et al, 2021 ).…”

“…In particular, Vimentin expression is highly reactivated during epithelial to mesenchymal transition (EMT), a process that occurs during both physiological tissue development/regeneration and pathological cancer progression towards metastasis. Noteworthy, a bioinformatic search for G4-repeats at proximal gene promoters, followed by GO analysis, highlighted an intriguing correlation between the functions of Vimentin and those of the genes containing putative Vimentin binding sites at their promoters ( Ceschi et al, 2022 ).…”

Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future Anticancer Therapeutic Applications

“…Studying the proteins that are able to selectively recognize G4 repeats could be a strategy to address the specific functions of these DNA structures. Pull-down experiments on nuclear extracts were performed to identify proteins that preferentially bind G4 repeats rather than isolated G4s ( Figure 6 ) [ 68 ]. Remarkably, it turns out that vimentin, an intermediate filament protein, can bind G4 repeats with high affinity.…”

“… Outline of a pull-down approach leading to the discovery of vimentin as a G4 repeat selective binder (adapted from [ 68 ]). …”