Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
Yang Wang, … , Norman Sharpless, Sandy Chang
Yang Wang, … , Norman Sharpless, Sandy Chang
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4489-4501. https://doi.org/10.1172/JCI69574.
View: Text | PDF
Research Article Cell biology Article has an altmetric score of 11

p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses

  • Text
  • PDF
Abstract

Dysfunctional telomeres limit cellular proliferative capacity by activating the p53-p21– and p16INK4a-Rb–dependent DNA damage responses (DDRs). The p16INK4a tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo. While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16INK4a in response to telomere dysfunction remains unclear. Here, we generated protection of telomeres 1b p16–/– mice (Pot1bΔ/Δ;p16–/–) to address the function of p16INK4a in the setting of telomere dysfunction in vivo. We found that deletion of p16INK4a accelerated organ impairment and observed functional defects in highly proliferative organs, including the hematopoietic system, small intestine, and testes. Pot1bΔ/Δ;p16–/– hematopoietic cells exhibited increased telomere loss, increased chromosomal fusions, and telomere replication defects. p16INK4a deletion enhanced the activation of the ATR-dependent DDR in Pot1bΔ/Δ hematopoietic cells, leading to p53 stabilization, increased p21-dependent cell cycle arrest, and elevated p53-dependent apoptosis. In contrast to p16INK4a, deletion of p21 did not activate ATR, rescued proliferative defects in Pot1bΔ/Δ hematopoietic cells, and significantly increased organismal lifespan. Our results provide experimental evidence that p16INK4a exerts protective functions in proliferative cells bearing dysfunctional telomeres.

Authors

Yang Wang, Norman Sharpless, Sandy Chang

×

Figure 2

Increased proliferative defects in DK hematopoietic cells.

Options: View larger image (or click on image) Download as PowerPoint
Increased proliferative defects in DK hematopoietic cells.
(A) Quantific...
(A) Quantification of total nucleated BM cells isolated from mice of the indicated genotypes (left panel), representative images from BM mononuclear cell colony-forming assays (CFAs) in M3434 media (middle panel) and quantification of CFAs from mice of the indicated genotypes at 8 to 10 weeks of age (right panel). Each genotype consists of cells isolated from a minimum of 4 mice. Error bars represent the SEM. (B) Same as A, except cells were isolated from mice of the indicated genotypes at 20 to 25 weeks of age. Error bars represent the SEM. (C) Representative Y chromosome–specific probe FISH images of BM transplantation experiments. Arrow points to labeled Y chromosome (gray); DAPI-stained cell nuclei. For A and B, a two-tailed Student’s t test was used to calculate statistical significance.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Posted by 1 X users
65 readers on Mendeley
See more details