Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

Yanhui Li, Gang Zhou, Ivone G. Bruno, Ning Zhang, Sei Sho, Enzo Tedone, Tsung Po Lai, John P. Cooke, Jerry W. Shay

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is characterized by accelerated senescence due to a de novo mutation in the LMNA gene. The mutation produces an abnormal lamin A protein called progerin that lacks the splice site necessary to remove a farnesylated domain. Subsequently, progerin accumulates in the nuclear envelope, disrupting nuclear architecture, chromatin organization, and gene expression. These alterations are often associated with rapid telomere erosion and cellular aging. Here, we further characterize the cellular and molecular abnormalities in HGPS cells and report a significant reversal of some of these abnormalities by introduction of in vitro transcribed and purified human telomerase (hTERT) mRNA. There is intra-individual heterogeneity of expression of telomere-associated proteins DNA PKcs/Ku70/Ku80, with low-expressing cells having shorter telomeres. In addition, the loss of the heterochromatin marker H3K9me3 in progeria is associated with accelerated telomere erosion. In HGPS cell lines characterized by short telomeres, transient transfections with hTERT mRNA increase telomere length, increase expression of telomere-associated proteins, increase proliferative capacity and cellular lifespan, and reverse manifestations of cellular senescence as assessed by β-galactosidase expression and secretion of inflammatory cytokines. Unexpectedly, mRNA hTERT also improves nuclear morphology. In combination with the farnesyltransferase inhibitor (FTI) lonafarnib, hTERT mRNA promotes HGPS cell proliferation. Our findings demonstrate transient expression of human telomerase in combination with FTIs could represent an improved therapeutic approach for HGPS.

Original languageEnglish (US)
Article numbere12979
JournalAging Cell
Volume18
Issue number4
DOIs
StatePublished - Aug 2019

Keywords

  • Hutchinson-Gilford progeria syndrome
  • RNA therapy
  • aging
  • telomerase
  • telomeres

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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