Spatial and temporal organization of the genome represents an additional step in the regulation of nuclear functions. The nuclear lamina, a polymeric meshwork formed by
lamins (A/C and B type) and
lamin-associated
proteins, plays a key role in the maintenance of genome localization, structure and function. Specifically, mutations in the LMNA gene encoding
lamins A/C or changes in its expression, either upregulation or silencing, are associated with defects in DNA replication, transcription and repair, as well as alterations in epigenetic modifications of
chromatin. These data, together with the fact that defects in A-type
lamins are associated with a whole variety of degenerative disorders,
premature aging syndromes and
cancer, support the notion that these
proteins operate as caretakers of the genome. However, our understanding of their functions is limited due to the lack of well-defined mechanisms behind the
genomic instability observed in
lamin-related diseases. Here, we summarize our recent discovery of new pathways that are affected by the loss of A-type
lamins. In particular, we found that A-type
lamins control transcription and degradation of
proteins with key roles in cell cycle regulation and
DNA double-strand breaks (DSBs) repair by non-homologous end-joining (NHEJ) and homologous-recombination (HR). Importantly, the
proteins regulated by A-type
lamins--Rb family members, 53BP1, BRCA1 and RAD51--exert
tumor suppressor functions, with their loss being associated with
cancer susceptibility. Moreover, our studies revealed novel pathways that contribute to
genomic instability and that can be activated in disease states independent of the status of A-type
lamins.