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(Δ8-11/Δ8-11)) 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(Δ9/Δ9)) results in a
progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Δ9/Δ9) 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(Δ9/Δ9) MEFs do not present
genomic instability, and expression of mutant
lamin A Δexon9 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(Δ8-11/Δ8-11) 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.