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

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.
AuthorsAbena 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
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 10 Issue 15 Pg. 2549-60 (Aug 01 2011) ISSN: 1551-4005 [Electronic] United States
PMID21701264 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • BRCA1 Protein
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • E2F4 Transcription Factor
  • Lamin Type A
  • RNA, Small Interfering
  • Retinoblastoma-Like Protein p130
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Rad51 Recombinase
Topics
  • Animals
  • BRCA1 Protein (metabolism)
  • Cell Line
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone (metabolism)
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA-Binding Proteins (metabolism)
  • E2F4 Transcription Factor (metabolism)
  • Homologous Recombination
  • Humans
  • Lamin Type A (antagonists & inhibitors, metabolism)
  • Mice
  • RNA Interference
  • RNA, Small Interfering (metabolism)
  • Rad51 Recombinase (metabolism)
  • Radiation, Ionizing
  • Retinoblastoma-Like Protein p130 (metabolism)
  • Tumor Suppressor p53-Binding Protein 1

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