Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2015
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| Online Access: | https://hdl.handle.net/10356/81002 http://hdl.handle.net/10220/39046 |
| _version_ | 1826114099941998592 |
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| author | Chojnowski, Alexandre Ong, Peh Fern Wong, Esther S. M. Lim, John S. Y. Mutalif, Rafidah A. Navasankari, Raju Dutta, Bamaprasad Yang, Henry Liow, Yi Y. Sze, Siu Kwan Boudier, Thomas Wright, Graham D. Colman, Alan Burke, Brian Stewart, Colin L. Dreesen, Oliver |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Chojnowski, Alexandre Ong, Peh Fern Wong, Esther S. M. Lim, John S. Y. Mutalif, Rafidah A. Navasankari, Raju Dutta, Bamaprasad Yang, Henry Liow, Yi Y. Sze, Siu Kwan Boudier, Thomas Wright, Graham D. Colman, Alan Burke, Brian Stewart, Colin L. Dreesen, Oliver |
| author_sort | Chojnowski, Alexandre |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:33:59Z |
| format | Journal Article |
| id | ntu-10356/81002 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:33:59Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/810022023-02-28T16:59:30Z Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria Chojnowski, Alexandre Ong, Peh Fern Wong, Esther S. M. Lim, John S. Y. Mutalif, Rafidah A. Navasankari, Raju Dutta, Bamaprasad Yang, Henry Liow, Yi Y. Sze, Siu Kwan Boudier, Thomas Wright, Graham D. Colman, Alan Burke, Brian Stewart, Colin L. Dreesen, Oliver School of Biological Sciences 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2015-12-11T03:54:25Z 2019-12-06T14:19:19Z 2015-12-11T03:54:25Z 2019-12-06T14:19:19Z 2015 Journal Article Chojnowski, A., Ong, P. F., Wong, E. S. M., Lim, J. S. Y., Mutalif, R. A., Navasankari, R., et al. (2015). Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria. eLife, 4, e07759-. 2050-084X https://hdl.handle.net/10356/81002 http://hdl.handle.net/10220/39046 10.7554/eLife.07759 26312502 en eLife © Copyright Chojnowski et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. 21 p. application/pdf |
| spellingShingle | Chojnowski, Alexandre Ong, Peh Fern Wong, Esther S. M. Lim, John S. Y. Mutalif, Rafidah A. Navasankari, Raju Dutta, Bamaprasad Yang, Henry Liow, Yi Y. Sze, Siu Kwan Boudier, Thomas Wright, Graham D. Colman, Alan Burke, Brian Stewart, Colin L. Dreesen, Oliver Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title | Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title_full | Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title_fullStr | Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title_full_unstemmed | Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title_short | Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria |
| title_sort | progerin reduces lap2α telomere association in hutchinson gilford progeria |
| url | https://hdl.handle.net/10356/81002 http://hdl.handle.net/10220/39046 |
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