Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins
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 re...
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Frontiers Media S.A.
2025-05-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10537/full |
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| author | Muriel W. Lambert |
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| author_sort | Muriel W. Lambert |
| collection | DOAJ |
| description | 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, μ-calpain, 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. |
| format | Article |
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| institution | OA Journals |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Experimental Biology and Medicine |
| spelling | doaj-art-ed89a343c2304980b48ea13bb0f3e02d2025-08-20T01:48:26ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-05-0125010.3389/ebm.2025.1053710537Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteinsMuriel W. LambertNonerythroid 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, μ-calpain, 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.https://www.ebm-journal.org/articles/10.3389/ebm.2025.10537/fullalpha spectrinDNA repairDNA interstrand crosslinksμ-calpainFanconi anemia proteins |
| spellingShingle | Muriel W. Lambert Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins Experimental Biology and Medicine alpha spectrin DNA repair DNA interstrand crosslinks μ-calpain Fanconi anemia proteins |
| title | Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins |
| title_full | Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins |
| title_fullStr | Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins |
| title_full_unstemmed | Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins |
| title_short | Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins |
| title_sort | critical role of alpha spectrin in dna repair the importance of μ calpain and fanconi anemia proteins |
| topic | alpha spectrin DNA repair DNA interstrand crosslinks μ-calpain Fanconi anemia proteins |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10537/full |
| work_keys_str_mv | AT murielwlambert criticalroleofalphaspectrinindnarepairtheimportanceofmcalpainandfanconianemiaproteins |