TGF-β-induced fibrotic stress increases G-quadruplex formation in human fibroblasts

Priyanka Toshniwal, Michelle Nguyen, Aurore Guédin, Helena Viola, Diwei Ho, Yongeun Kim, Uditi Bhatt, Charles S. Bond, Livia Hool, Laurence H. Hurley, Jean Louis Mergny, Mark Fear, Fiona Wood, Swaminathan K. Iyer, Nicole M. Smith

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF-β-induced fibrotic stress increases formation of the dynamic secondary DNA structures called G-quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G-quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti-fibrotic compound. In addition, we identify G-quadruplex-forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G-quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G-quadruplexes and scar formation that may lead to novel therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)3149-3161
Number of pages13
JournalFEBS Letters
Volume593
Issue number22
DOIs
StatePublished - Nov 1 2019

Keywords

  • G-quadruplex
  • G-quartet
  • G-tetraplex
  • G4 DNA
  • Scar formation

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Toshniwal, P., Nguyen, M., Guédin, A., Viola, H., Ho, D., Kim, Y., Bhatt, U., Bond, C. S., Hool, L., Hurley, L. H., Mergny, J. L., Fear, M., Wood, F., Iyer, S. K., & Smith, N. M. (2019). TGF-β-induced fibrotic stress increases G-quadruplex formation in human fibroblasts. FEBS Letters, 593(22), 3149-3161. https://doi.org/10.1002/1873-3468.13658