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      Nuclear alpha spectrin: Critical roles in DNA interstrand cross-link repair and genomic stability

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          Abstract

          Non-erythroid alpha spectrin (αIISp) is a structural protein which we have shown is present in the nucleus of human cells. It interacts with a number of nuclear proteins such as actin, lamin, emerin, chromatin remodeling factors, and DNA repair proteins. αIISp’s interaction with DNA repair proteins has been extensively studied. We have demonstrated that nuclear αIISp is critical in DNA interstrand cross-link (ICL) repair in S phase, in both genomic (non-telomeric) and telomeric DNA, and in maintenance of genomic stability following ICL damage to DNA. We have proposed that αIISp acts as a scaffold aiding to recruit repair proteins to sites of damage. This involvement of αIISp in ICL repair and telomere maintenance after ICL damage represents new and critical functions for αIISp. These studies have led to development of a model for the role of αIISp in DNA ICL repair. They have been aided by examination of cells from patients with Fanconi anemia (FA), a repair-deficient genetic disorder in which a deficiency in αIISp leads to defective ICL repair in genomic and telomeric DNA, telomere dysfunction, and chromosome instability following DNA ICL damage. We have shown that loss of αIISp in FA cells is due to increased breakdown by the protease, µ-calpain. Importantly, we have demonstrated that this deficiency can be corrected by knockdown of µ-calpain and restoring αIISp levels to normal. This corrects a number of the phenotypic deficiencies in FA after ICL damage. These studies suggest a new and unexplored direction for therapeutically restoring genomic stability in FA cells and for correcting numerous phenotypic deficiencies occurring after ICL damage. Developing a more in-depth understanding of the importance of the interaction of αIISp with other nuclear proteins could significantly enhance our knowledge of the consequences of loss of αIISp on critical nuclear processes.

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          Author and article information

          Journal
          Exp Biol Med (Maywood)
          Exp. Biol. Med. (Maywood)
          EBM
          spebm
          Experimental Biology and Medicine
          SAGE Publications (Sage UK: London, England )
          1535-3702
          1535-3699
          01 August 2016
          September 2016
          : 241
          : 15
          : 1621-1638
          Affiliations
          Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
          Author notes
          Muriel W Lambert. Email: mlambert@ 123456njms.rutgers.edu
          Article
          PMC4999628 PMC4999628 4999628 10.1177_1535370216662714
          10.1177/1535370216662714
          4999628
          27480253
          © 2016 by the Society for Experimental Biology and Medicine
          Categories
          Biochemistry & Molecular Biology

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