Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A

Abstract Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does n...

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Autores principales:	So-mi Kang, Min-Ho Yoon, Su-Jin Lee, Jinsook Ahn, Sang Ah Yi, Ki Hong Nam, Soyoung Park, Tae-Gyun Woo, Jung-Hyun Cho, Jaecheol Lee, Nam-Chul Ha, Bum-Joon Park
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/01b8eaca40fd400584abe15784946828
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spelling	oai:doaj.org-article:01b8eaca40fd400584abe157849468282021-12-02T13:41:22ZHuman WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A10.1038/s41598-021-88325-12045-2322https://doaj.org/article/01b8eaca40fd400584abe157849468282021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88325-1https://doaj.org/toc/2045-2322Abstract Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.So-mi KangMin-Ho YoonSu-Jin LeeJinsook AhnSang Ah YiKi Hong NamSoyoung ParkTae-Gyun WooJung-Hyun ChoJaecheol LeeNam-Chul HaBum-Joon ParkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q So-mi Kang Min-Ho Yoon Su-Jin Lee Jinsook Ahn Sang Ah Yi Ki Hong Nam Soyoung Park Tae-Gyun Woo Jung-Hyun Cho Jaecheol Lee Nam-Chul Ha Bum-Joon Park Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
description	Abstract Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.
format	article
author	So-mi Kang Min-Ho Yoon Su-Jin Lee Jinsook Ahn Sang Ah Yi Ki Hong Nam Soyoung Park Tae-Gyun Woo Jung-Hyun Cho Jaecheol Lee Nam-Chul Ha Bum-Joon Park
author_facet	So-mi Kang Min-Ho Yoon Su-Jin Lee Jinsook Ahn Sang Ah Yi Ki Hong Nam Soyoung Park Tae-Gyun Woo Jung-Hyun Cho Jaecheol Lee Nam-Chul Ha Bum-Joon Park
author_sort	So-mi Kang
title	Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
title_short	Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
title_full	Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
title_fullStr	Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
title_full_unstemmed	Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A
title_sort	human wrn is an intrinsic inhibitor of progerin, abnormal splicing product of lamin a
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/01b8eaca40fd400584abe15784946828
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_version_	1718392536661229568

Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A

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