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

Ki Hong Nam,Jinsook Ahn,Min-Ho Yoon,Jung-Hyun Cho,So-Mi Kang,Soyoung Park,Sang Ah Yi,Jaecheol Lee,Nam-Chul Ha,Tae-Gyun Woo,Su-Jin Lee,Bum-Joon Park

doi:10.1038/s41598-021-88325-1

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.

Highlights

Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase
We found that a large portion of gene sets were commonly upregulated or downregulated in Hutchinson Gilford progeria syndrome (HGPS) and WRN cells compared to normal young cells
Compared to N9 fibroblasts, 881 genes were altered in both HGPS and WRN cells (Fig. 1D and Fig. S2D and S2E) and their functions were categorized into nine elements (Fig. 1E), which were mainly involved in cell cycle progression

Summary

Introduction

Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. WRN deficiency can promote telomere fusion and r ecombination[19,20] This event is observed in Wrn-deficient mouse c ells[20], (and Wrn-deleted mice have normal phenotypes, similar to those of wild-type m ice21), indicating that telomere dysregulation is not a direct reason for premature aging. Yellow boxes indicate gene sets downregulated in both WRN and HGPS cells compared to normal fibroblasts (N9). We found that progerin strongly binds to wild-type lamin A, creating an abnormal nuclear shape and promoting the aging p rocess[32]. These previous reports show that, defects in lamin A regulation are closely involved in pathological and physiological aging progression. In this report, we explored a novel function of WRN in the aging process and introduced an inhibitor of progerin as an effective drug candidate for WRN patients

Methods

Results

Conclusion