• Open Access

Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson–Gilford progeria syndrome

Authors

  • Hui Tang,

    1. Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
    2. Department of Biochemistry and Molecular Biology, West China Center of Medical Sciences, Sichuan University, Chengdu, China
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    • The authors contributed equally to this work.

  • Benjamin Hilton,

    1. Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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    • The authors contributed equally to this work.

  • Phillip R. Musich,

    1. Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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  • Ding Zhi Fang,

    1. Department of Biochemistry and Molecular Biology, West China Center of Medical Sciences, Sichuan University, Chengdu, China
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  • Yue Zou

    1. Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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Yue Zou, Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Tel.: (423) 439 2124; fax: (423) 439 2030; e-mail: zouy@etsu.edu

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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