A-type
lamins are emerging as regulators of nuclear organization and function. Changes in their expression are associated with
cancer and mutations are linked to degenerative diseases -
laminopathies-. Although a correlation exists between alterations in
lamins and
genomic instability, the molecular mechanisms remain largely unknown. We previously found that loss of A-type
lamins leads to degradation of
53BP1 protein and defective long-range non-homologous end-joining (NHEJ) of dysfunctional telomeres. Here, we determined how loss of A-type
lamins affects the repair of short-range
DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). We find that
lamins deficiency allows activation of the DNA damage response, but compromises the accumulation of 53BP1 at IR-induced foci (IRIF), hindering the fast phase of repair corresponding to classical-NHEJ. Importantly, reconstitution of 53BP1 is sufficient to rescue long-range and short-range NHEJ. Moreover, we demonstrate an unprecedented role for A-type
lamins in the maintenance of homologous recombination (HR). Depletion of
lamins compromises HR by a mechanism involving transcriptional downregulation of BRCA1 and RAD51 by the repressor complex formed by the Rb family member p130 and E2F4. In line with the DNA repair defects,
lamins-deficient cells exhibit increased radiosensitivity. This study demonstrates that A-type
lamins promote
genomic stability by maintaining the levels of
proteins with key roles in
DNA DSBs repair by NHEJ and HR. Our results suggest that silencing of A-type
lamins by DNA methylation in some
cancers could contribute to the
genomic instability that drives
malignancy. In addition,
lamins-deficient
tumor cells could represent a good target for
radiation therapy.