title: 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.
authors.affiliation: Radiation and Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Abena B
authors.initials: AB
authors.lastname: Redwood
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Perkins
authors.forename: Robert P
authors.initials: RP
authors.lastname: Vanderwaal
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Biehl
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.forename: Lucia
authors.initials: L
authors.lastname: Morgado-Palacin
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Roti-Roti
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Junran
authors.initials: J
authors.lastname: Zhang
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D002460:Cell Line; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D050704:E2F4 Transcription Factor / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D034904:Lamin Type A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D034904:Lamin Type A; D034741:RNA, Small Interfering; D050717:Retinoblastoma-Like Protein p130; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D051135:Rad51 Recombinase