Cited by 52Nuclear Structure and FunctionDNA Repair MechanismsTelomeres, Telomerase, and Senescence

Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes

Open access
Hilton, Benjamin A., Liu, Ji, Cartwright, Brian M., Liu, Yiyong, Breitman, Maya, Wang, Youjie, Jones, Rowdy, Tang, Hui +3 more·2017·The FASEB Journal

Abstract

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene, resulting in production of a truncated farnesylated‐prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin‐induced DNA double‐strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds‐ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin‐induced apoptosis could be rescued by XPA, suggesting that XPA‐replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin‐induced genome instability and accelerated replicative senescence in HGPS.—Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., Zou, Y. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes. FASEB J. 31, 3882–3893 (2017). www.fasebj.org —Hilton, Benjamin A., Liu, Ji, Cartwright, Brian M., Liu, Yiyong, Breitman, Maya, Wang, Youjie, Jones, Rowdy, Tang, Hui, Rusinol, Antonio, Musich, Phillip R., Zou, Yue Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes. FASEB J. 31, 3882–3893 (2017)

Integrity signals

Registry

Crossref · 10.1096/fj.201700014r

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., & Zou, Y.
Affiliations
  • East Tennessee State University (US)
  • Sichuan University (CN)
  • Huazhong University of Science and Technology (CN)
  • Department of Biomedical Sciences J. H. Quillen College of Medicine East Tennessee State University Johnson City Tennessee USA
Corresponding author
Zou, Yue
Venue
The FASEB Journal
Publisher
Wiley
Published
2017-09
Volume
31
Issue
9
Pages
3882-3893
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
OpenAlex
W2614142082
Cited by
52
References
64
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 2
FWCI
3.02
Type
journal article
Language
en
Open access
Locations
  • The FASEB Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG031503)
  • Progeria Research Foundation
  • East Tennessee State University (E82083, E31231)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
progerin, Hutchinson-Gilford progeria syndrome, laminopathies, PCNA, XPA, replication fork collapse, DNA double-strand break repair, DNA damage response, genomic instability, replicative senescence, apoptosis, lamin A/C, progeroid syndromes, DNA damage tolerance
MeSH terms
Cells, Cultured, DNA Repair, Fibroblasts, Gene Expression Regulation, Histones, Humans, Mutation, Progeria, Apoptosis, Proliferating Cell Nuclear Antigen, Protein Subunits, Protein Transport, RNA, Small Interfering, Lamin Type A, Xeroderma Pigmentosum Group A Protein, DNA Breaks, Double-Stranded

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review