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 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.

Progerin, an Aberrant Spliced form of Lamin A, is a Potential Therapeutic Target for HGPS

“…Short hairpin RNA constructs were designed to target progerin mRNA and mutate pre-spliced LMNA mR-NAs with 1824 C->T mutations. The expression of shRNA using lentiviruses significantly decreased progerin expression and in turn led to the improvement of the abnormal nuclear morphology, the recovery of proliferative potential, and a reduction in senescent cells [96,97]. These findings justify the potential use of gene therapy for HGPS treatment.…”

“…Cellular progerin levels are correlated with the severity of the premature aging phenotype. Approximately 20 years ago, the specific knockdown of progerin mRNA by RNA interference was shown to alleviate cellular aging features [96,97]. Short hairpin RNA constructs were designed to target progerin mRNA and mutate pre-spliced LMNA mR-NAs with 1824 C->T mutations.…”

MUT-7 Provides Molecular Insight into the Werner Syndrome Exonuclease

“…WRN inactivation is selectively associated with the MSI-H status of cancer cells rather than the microsatellite stable (MSS) status of colorectal and endometrial cancer cell lines [ 10 ]. A relatively surprising finding was that gene expression analysis between WS cells and HGPS cells revealed very similar profiles [ 74 ]. Thus, a progerin inhibitor (SLC-D011) can improve the premature aging phenotypes of WRN iPSCs derived from fibroblasts and cardiac muscle cells [ 74 ].…”

“…A relatively surprising finding was that gene expression analysis between WS cells and HGPS cells revealed very similar profiles [ 74 ]. Thus, a progerin inhibitor (SLC-D011) can improve the premature aging phenotypes of WRN iPSCs derived from fibroblasts and cardiac muscle cells [ 74 ]. Moreover, these iPSC lines derived from a WS patient have shown the potential to correct mutations in the WRN gene by using the CRISPR/Cas9-mediated method [ 75 ].…”

Splicing Variants, Protein-Protein Interactions, and Drug Targeting in Hutchinson-Gilford Progeria Syndrome and Small Cell Lung Cancer

“…Furthermore, they extended the effect of Progerinin to Werner syndrome, a rare progressive genetic disorder that results from a functional defect of the human WRN protein, a member of the RecQ DNA helicase family [ 68 ]. The Progerin-inhibitor (SLC-D011) could ameliorate senescence in the fibroblasts and cardiomyocytes derived from Werner syndrome-iPSCs, suggesting that Progerin is able to accumulate and cause aging phenotype under WRN-deficient conditions and the phenomenon may be prevented by SLC-D011 [ 69 ]. Interestingly, under the natural aging process, Progerin can be produced and increased with age [ 47 , 70 ].…”