title: Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.
abstract: Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Alexandre
authors: A
authors: Chojnowski
authors: Cellular Ageing, Institute of Medical Biology, Singapore, Singapore.
authors: Peh Fern
authors: PF
authors: Ong
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Esther S M
authors: ES
authors: Wong
authors: Microscopy Unit, Institute of Medical Biology, Singapore, Singapore.
authors: John S Y
authors: JS
authors: Lim
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Rafidah A
authors: RA
authors: Mutalif
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Raju
authors: R
authors: Navasankari
authors: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors: Bamaprasad
authors: B
authors: Dutta
authors: Bioinformatics Core, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Henry
authors: H
authors: Yang
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Yi Y
authors: YY
authors: Liow
authors: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors: Siu K
authors: SK
authors: Sze
authors: Bioinformatics Institute, IPAL UMI 2955, Singapore, Singapore.
authors: Thomas
authors: T
authors: Boudier
authors: Microscopy Unit, Institute of Medical Biology, Singapore, Singapore.
authors: Graham D
authors: http://orcid.org/0000-0003-2362-1312
authors: GD
authors: Wright
authors: Stem Cell Disease Models, Institute of Medical Biology, Singapore, Singapore.
authors: Alan
authors: A
authors: Colman
authors: Nuclear Dynamics and Architecture, Institute of Medical Biology, Singapore, Singapore.
authors: Brian
authors: B
authors: Burke
authors: Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore.
authors: Colin L
authors: CL
authors: Stewart
authors: Cellular Ageing, Institute of Medical Biology, Singapore, Singapore.
authors: Oliver
authors: O
authors: Dreesen
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008853:Microscopy; D011371:Progeria / Q000473:pathology*; D011485:Protein Binding; D016615:Telomere / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2; C090764:prelamin A
keywords: LAP2 alpha; chromosomes; genes; human; lamin A; mouse; progeria; progerin; senescence; telomeres