Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes
Open accessAbstract
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)
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High Body Mass Index is Associated with Elevated Blood Levels of Progerin mRNA
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The impact of alterations in lamin A on genome integrity
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- 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
- PMC
- PMC5572696
- 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
- green
- europepmc.org
- 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
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