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Werner syndrome WRN helicase alters gene expression in a G-quadruplex DNA-dependent manner to antagonize a pro-senescence gene expression program

ABSTRACT: Werner syndrome (WS) is a human adult progeroid syndrome caused by loss-of-function mutations in the WRN RECQ helicase gene. We analyzed mRNA and miRNA expression in fibroblasts from WS patients and in fibroblasts depleted of WRN protein in order to determine the role of WRN in transcription regulation, and to identify genes and miRNAs that might drive WS disease pathogenesis. Genes altered in WS cells participate in cellular growth, proliferation and survival; in tRNA charging and in oncogenic signaling; and in connective tissue and developmental networks. Genes down-regulated in WS cells were highly enriched in Gquadruplex (G4) DNA motifs, indicating G4 motifs are physiologic substrates for WRN. In contrast, there was a remarkable, coordinate up-regulation of nearly all of the cytoplasmic tRNA synthetases and of genes associated with the senescence-associated secretory phenotype (SASP). These results identify canonical pathways that may drive the pathogenesis of Werner syndrome and associated disease risks.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE62877 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA266223

REPOSITORIES: GEO

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Project description:Our focus of research, the Werner protein, is one of disease-associated RecQ helicases. Its deficiency results in the Werner syndrome (WS), characterized by accelerated rate of mutation and the organism's inability to resolve a variety of genome-damaging events. Mutations in the WRN gene (also referred to as RECQ3 or RECQL2) don't appear to increase a person's susceptibility to DNA damage, and they alone do not cause the development of the disease. Instead they accelerate and exacerbate the disease that could develop even without this sensitizing mutation due to the damaging environmental agents. An important consequence of understanding the mechanism of a pathology is the ability to treat it more effectively, and even to prevent it in some cases. Aging research is extremely important considering the changing demographics worldwide, increased overall longevity and rise in elderly population. Understanding of the mechanisms that underlie aging and development of age-related disease due to genomic aberration can lead us to improved treatment and alleviated burden of age-related disease. Activity of proteins such as WRN suggests that the complex process of ageing is controlled by a conserved number of genes. However, mutations in a series of proteins do not suggest that their normal function is involved in promoting longevity. We are interested in understanding how normal function of this protein stalls senescence. In order to determine these mechanisms we study protein function in normal and diseased states with the use of proteomics. Resources that are currently available to us include modern analytical instrumentation, support from computational sciences, and access to rare biological samples. Our work is aimed at defining consistently associated proteins and post-translational modifications of WRN that are required or are causal for its function in human cells. This knowledge will increase our understanding of WS pathogenesis and provide insight into novel strategies to alter the progression of WS or associated diseases such as ASCVD, cancer, diabetes, and osteoporosis.

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Werner syndrome WRN helicase alters gene expression in a G-quadruplex DNA-dependent manner to antagonize a pro-senescence gene expression program

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