Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson–Gilford progeria syndrome
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Summary: Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder because of a LMNA gene mutation that produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here, we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ∼ 75 kDa, which appears to be defective in loading proliferating cell nuclear antigen (PCNA) and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Because of the crucial role of RFC in DNA replication, our findings provide a mechanistic interpretation for the observed early replicative arrest and premature aging phenotypes of HPGS and may lead to novel strategies in HGPS treatment. Furthermore, this unique truncated form of RFC1 may serve as a potential marker for HGPS.
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These DNA metabolism deficiencies correlate with proteolytic truncation of RFC1 and sequestration of PCNA in a complex with progerin.
“These DNA metabolism deficiencies also correlate with a proteolytic truncation of replication factor C1 (RFC1) 115 and a sequestration of proliferating cell nuclear antigen (PCNA) in a complex with progerin (Hilton et al., private communication).”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [115]
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References 11 · Cited by 23
- Authors
- Tang, H., Hilton, B., Musich, P. R., Fang, D. Z., & Zou, Y.
- Affiliations
- East Tennessee State University (US)
- Sichuan University (CN)
- Corresponding author
- Zou, Yue
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-01-13
- Volume
- 11
- Issue
- 2
- Pages
- 363-365
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3306506
- OpenAlex
- W2132773091
- Cited by
- 23
- References
- 11
- Citations by year
- 2024: 1 · 2022: 4 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 0.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- Funders
- National Institute on Aging (AG031503, R03AG031503)
- 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
- Hutchinson-Gilford progeria syndrome, replication factor C, RFC1, progerin, LMNA mutations, serine protease cleavage, DNA replication, premature aging, diagnostic biomarkers
- MeSH terms
- Cell Line, Humans, Progeria, Replication Protein C, Prenylation
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