Review
Exp. Biol. Med.
Sec. Biochemistry and Molecular Biology
Volume 250 - 2025 | doi: 10.3389/ebm.2025.10537
This article is part of the IssueBreakthroughs in Biomedical Research: Review/Minireview IssueView all 4 articles
Critical role of alpha spectrin in DNA repair: The importance of μcalpain and Fanconi anemia proteins
- New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, United States
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Nonerythroid spectrins are proteins important in maintaining the structural integrity and flexibility of the cell and nuclear membranes and are essential for a number of functionally important cellular processes. One of these proteins, nonerythroid α spectrin (αSpII), plays a critical role in DNA repair, specifically repair of DNA interstrand crosslinks (ICLs), where it acts as a scaffold, recruiting repair proteins to sites of damage. Loss or breakdown of αSpII is an important factor in a number of disorders.One of these is Fanconi anemia (FA), a genetic disorder characterized by bone marrow failure, chromosome instability, cancer predisposition, congenital abnormalities and a defect in DNA ICL repair. Significantly, breakdown of αSpII occurs in cells from a number of FA complementation groups, due to excessive cleavage by the protease, μcalpain, leading to defective repair of DNA ICLs in telomeric and non-telomeric DNA.Knockdown of μ-calpain in FA cells by μ-calpain siRNA results in restoration of αSpII levels to normal and repair of DNA ICLs in telomeric and non-telomeric DNA, demonstrating the importance of αSpII stability in the repair process. It is hypothesized that there is a mechanistic link between excessive cleavage of αSpII by μ-calpain and defective DNA ICL repair in FA and that FA proteins, which are deficient in FA, play a key role in maintaining the stability of αSpII and preventing its cleavage by μ-calpain. All of these events are proposed to be important key factors involved in the pathophysiology of FA and suggest new avenues for potential therapeutic intervention.
Keywords: alpha spectrin, DNA repair, DNA interstrand crosslinks, μ-calpain, Fanconi anemia proteins
Received: 21 Feb 2025; Accepted: 17 Apr 2025.
Copyright: © 2025 Lambert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Muriel w Lambert, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, United States
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