Novel roles for A‐type lamins in telomere biology and the DNA damage response pathway |
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| Authors: | Stephanie M Perkins Bart Vermolen Daniel Lichtensztejin David A Grotsky Lucia Morgado‐Palacin Eric J Gapud Barry P Sleckman Teresa Sullivan Julien Sage Colin L Stewart Sabine Mai Susana Gonzalo |
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| Affiliation: | 1. Department of Radiation Oncology and Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA;2. Biophysical Engineering Group, Faculty of Science and Technology, University of Twente, The Netherlands;3. Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada;4. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA;5. Cancer and Developmental Biology Laboratory, NCI at Frederick, Frederick, MD, USA;6. Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA;7. Institute of Medical Biology, 8A Biomedical Grove #06‐40, Immunos Singapore, Singapore |
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| Abstract: | A‐type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A‐type lamins and how they contribute to disease are poorly understood. Here, we show that A‐type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A‐type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A‐type lamins are necessary for the processing of dysfunctional telomeres by non‐homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A‐type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin‐related diseases. |
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| Keywords: | A‐type lamins DNA damage response genomic instability nuclear organization telomeres |
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