Journal
NUCLEUS-AUSTIN
Volume 4, Issue 5, Pages 410-419Publisher
LANDES BIOSCIENCE
DOI: 10.4161/nucl.26873
Keywords
lamins; HGPS; DNA repair; chromatin; telomeres; genomic instability
Categories
Funding
- NIGMS [RO1 GM094513-01]
- DOD BCRP Idea Award [BC110089]
- RDA from Siteman Cancer Center
- St Louis University
- AHA
- CDMRP [BC110089, 545454] Funding Source: Federal RePORTER
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Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8-11 (Lmna(Delta 8-11/Delta 8-11)) exhibit alterations in telomere biology and DNA repair caused by cathepsin L-mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8-11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna(Delta 9/Delta 9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Delta 9/Delta 9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna(Delta 9/Delta 9) MEFs do not present genomic instability, and expression of mutant lamin A Delta exon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna(Delta 8-11/Delta 8-11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability.
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