Home > Press > How cells repair DNAs protective barrier: a pathway to address a rare genetic disorder characterized by rapid aging in children
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| Delayed repair of nuclear envelope rupture in HGPS cells
Credit © Kono, et al., 2024. Published by Oxford University Press on behalf of National Academy of Sciences. |
Abstract:
Researchers at Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have discovered how a protein called lamin A helps repair the protective barrier around a cell’s DNA. The findings reveal lamin A’s unique role and its potential for treating Hutchinson-Gilford Progeria Syndrome, a rare disorder that causes premature aging.
How cells repair DNAs protective barrier: a pathway to address a rare genetic disorder characterized by rapid aging in children
Kanazawa, Japan | Posted on December 13th, 2024
The nuclear envelope (NE) is a vital barrier that protects the cells genetic material. It is supported by the nuclear lamina (NL), a fibrous protein network composed of lamins, including lamin A (LA) and lamin C (LC). Mechanical stress or genetic abnormalities can cause ruptures in the NE, exposing the genetic material to damage. While lamin C rapidly accumulates at NE rupture sites to facilitate repair, lamin A exhibits slower and weaker localization.
This slower response poses significant challenges, especially in diseases like HutchinsonGilford Progeria Syndrome (HGPS). In HGPS, a mutation in the LMNA gene produces progerin, a defective variant of lamin A that remains permanently associated with the NE and disrupts repair mechanisms (Fig. 1). Because progerins impaired mobility reduces the reserve pool available for repair, cellular damage could be further compounded, contributing to accelerated aging symptoms in patients.
An international team of researchers led by Takeshi Shimi at the NanoLSI, Kanazawa University, aimed to solve a critical question: Why does lamin A localize more slowly to NE rupture sites compared to lamin C, and how does this difference impact nuclear stability in both normal and diseased states? Specifically, they sought to understand how lamin A’s unique tail region and the post-translational modifications, such as farnesylation, influence its localization and functionality.
Key Findings
Lamin A’s Tail Region
The researchers have identified specific sequences in lamin As tail region, termed “Lamin A-Characteristic Sequences” (LACS1 and LACS2) that inhibit its rapid localization to rupture sites (Fig.2).
Progerin’s Impact in HGPS
Progerins defective structure leads to its permanent retention at the NE, reducing the nucleoplasmic pool of lamin A required for efficient NE repair. This delayed response contributes to nuclear instability and cellular aging.
Therapeutic Potential
A farnesyltransferase inhibitor (FTI), lonafarnib (Zokinvy) improves progerin and lamin A mobility and increase its nucleoplasmic availability, significantly enhancing NE repair in both healthy and HGPS models (Fig.3). This drug is approved in the United States, Europe, and Japan for the treatment of patients with HGPS.
This study bridges a critical gap in our understanding of Lamin A’s role in nuclear repair. It provides actionable insights for developing therapies targeting conditions where nuclear instability is a hallmark, such as HGPS, say the authors.
Glossary
Nuclear Envelope (NE): A double membrane that encloses the nucleus, protecting the genetic material.
Nuclear Lamina (NL): A fibrous network inside the nucleus that provides structural support and regulates gene expression.
Lamin A (LA): A structural protein in the nuclear lamina critical for maintaining nuclear envelope stability.
Hutchinson-Gilford Progeria Syndrome (HGPS): A genetic disorder caused by a mutation in the LMNA gene, leading to the production of progerin, a defective lamin A variant.
Farnesylation: A lipid modification of proteins like Ras, crucial for their localization and function.
Farnesyltransferase Inhibitors (FTIs): Drugs that block farnesylation, showing promise in restoring progerin and lamin A functionality.
Author acknowledgements
We thank Biomaterials Analysis Division, Open Facility Center (OFC) of Tokyo Institute of Technology for nucleotide sequencing and sharing research equipment, especially Carl Zeiss ElyraS1/Airyscan/LSM780 is shared in MEXT Project Grant Number JPMXS0440200022. We also thank the Cellular Imaging Core Facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Medical Center for technical support.
This work was supported by JSPS KAKENHI Grant Numbers JP20KK0158 (to T.S., Y.K., K.M. and H.K.), JP20K06617 (to T.S.), and JP18H05527 and JP21H04764 (to H.K.). This work was also supported by MEXT (World Premier International Research Center Initiative [WPI]). The generation and validation of the anti-murine progerin antibody was funded by the Wellcome Trust (098291/Z/12/Z to S.N.) and the British Heart Foundation (FS/IBSRF/22/25121 to L.R.).
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About Kanazawa University
As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.
The University is located on the coast of the Sea of Japan in Kanazawa a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.
About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University
Understanding nanoscale mechanisms of life phenomena by exploring uncharted nano-realms.
Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale.
https://nanolsi.kanazawa-u.ac.jp/en/
About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan’s Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
See the latest research news from the centers at the WPI News Portal: https://www.eurekalert.org/newsportal/WPI
Main WPI program site: www.jsps.go.jp/english/e-toplevel
For more information, please click here
Contacts:
Kimie Nishimura
Kanazawa University
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