A role for keratin 17 during DNA damage response and tumor initiation

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2020150118. doi: 10.1073/pnas.2020150118.

Abstract

High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.

Keywords: DNA damage; intermediate filament; keratin; skin; tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / administration & dosage
  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Active Transport, Cell Nucleus
  • Animals
  • Carcinogenesis / chemically induced
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinoma / chemically induced
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Cell Nucleus / metabolism
  • Cell Survival / genetics
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Repair*
  • Female
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Intravital Microscopy
  • Keratin-17 / genetics
  • Keratin-17 / metabolism*
  • Keratinocytes
  • Keratins / genetics
  • Keratins / metabolism*
  • Male
  • Mice, Knockout
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / pathology
  • Time-Lapse Imaging

Substances

  • KRT17 protein, human
  • Keratin-17
  • Krt17 protein, mouse
  • 9,10-Dimethyl-1,2-benzanthracene
  • Keratins