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.
Description
A dual role for A-type lamins in DNA double-stran... [Cell Cycle. 2011] - PubMed - NCBI
%0 Journal Article
%1 redwood2011atype
%A Redwood, A B
%A Perkins, S M
%A Vanderwaal, R P
%A Feng, Z
%A Biehl, K J
%A Gonzalez-Suarez, I
%A Morgado-Palacin, L
%A Shi, W
%A Sage, J
%A Roti-Roti, J L
%A Stewart, C L
%A Zhang, J
%A Gonzalo, S
%D 2011
%J Cell Cycle
%K dnadamage lamin phd
%N 15
%P 2549--2560
%T A dual role for A-type lamins in DNA double-strand break repair
%U http://www.ncbi.nlm.nih.gov/pubmed/21701264
%V 10
%X 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.
@article{redwood2011atype,
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.},
added-at = {2012-08-27T16:42:59.000+0200},
author = {Redwood, A B and Perkins, S M and Vanderwaal, R P and Feng, Z and Biehl, K J and Gonzalez-Suarez, I and Morgado-Palacin, L and Shi, W and Sage, J and Roti-Roti, J L and Stewart, C L and Zhang, J and Gonzalo, S},
biburl = {https://www.bibsonomy.org/bibtex/2e7a26008c48d54040960d428930fcdcf/bkoch},
description = {A dual role for A-type lamins in DNA double-stran... [Cell Cycle. 2011] - PubMed - NCBI},
interhash = {24a407ccd164e8bab6f64a02b5e7697a},
intrahash = {e7a26008c48d54040960d428930fcdcf},
journal = {Cell Cycle},
keywords = {dnadamage lamin phd},
month = aug,
number = 15,
pages = {2549--2560},
pmid = {21701264},
timestamp = {2012-08-27T16:42:59.000+0200},
title = {A dual role for A-type lamins in DNA double-strand break repair},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21701264},
volume = 10,
year = 2011
}