A dual role for A-type lamins in DNA double-strand break repair

Abena B. Redwood, Stephanie M. Perkins, Robert P. Vanderwaal, Zhihui Feng, Kenneth J. Biehl, Ignacio Gonzalez-Suarez, Lucia Morgado-Palacin, Wei Shi, Julien Sage, Joseph L. Roti-Roti, Colin L. Stewart, Junran Zhang, Susana Gonzalo

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2549-2560
Number of pages12
JournalCell Cycle
Volume10
Issue number15
DOIs
StatePublished - Aug 1 2011

Keywords

  • DNA repair
  • Homologous recombination
  • Lamins
  • Non-homologous end-joining
  • Radiosensitivity
  • Telomeres

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