title: Functional Significance of Nuclear α Spectrin.
abstract: Nonerythroid alpha spectrin (αIISp) interacts in the nucleus with an array of different proteins indicating its involvement in a number of diverse functions. However, the significance of these interactions and their functional importance has been a relatively unexplored area. The best documented role of nuclear αIISp is in DNA repair where it is critical for repair of DNA interstrand cross-links (ICLs), acting as a scaffold recruiting proteins to sites of damage in genomic and telomeric DNA. A deficiency in αIISp can importantly impact DNA ICL repair as is seen in cells from patients with the genetic disorder, Fanconi anemia (FA), where loss of αIISp leads to not only defects in repair of both genomic and telomeric DNA but also to telomere dysfunction and chromosome instability. This previously unexplored link between αIISp and telomere function is important in developing an understanding of maintenance of genomic stability after ICL damage. In FA cells, these defects in chromosome instability after ICL damage can be corrected when levels of αIISp are returned to normal by knocking down μ-calpain, a protease which cleaves αIISp. These studies suggest a new direction for correcting a number of the phenotypic defects in FA and could serve as a basis for therapeutic intervention. More in depth, examination of the interactions of αIISp with other proteins in the nucleus is of major importance in development of insights into the interacting key elements involved in the diverse processes occurring in the nucleus and the consequences loss of αIISp has on them.
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, New Jersey, 07103.
authors.forename: Muriel W
authors.initials: MW
authors.lastname: Lambert
mesh_terms: D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D043171:Chromosomal Instability; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D013049:Spectrin
chemical_list: D002154:Calpain; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D013049:Spectrin; C449002:mu-calpain
keywords: CHROMOSOME INSTABILITY; CHROMOSOME STABILITY; DNA DAMAGE; DNA INTERSTRAND CROSS-LINKS; DNA REPAIR; FANCG; FANCONI ANEMIA; FANCONI ANEMIA PROTEINS; NONERYTHROID ALPHA SPECTRIN; NUCLEAR SPECTRIN; SH3 DOMAINS; SPECTRIN CLEAVAGE; TELOMERE DYSFUNCTION; TELOMERE SIGNAL-FREE ENDS; TELOMERES; TRF1 AND TRF2; XPF; μ-CALPAIN