Roles of Werner syndrome protein in protection of genome integrity

Abstract

OverviewWerner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans (see additional reviews in this issue), as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster [1]. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging [1][2][3][4][5]. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance [1][2][3][4][5][6]. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions [1,2,7]. Many of these functions of WRN in genome maintenance, as well as the clinical characteristics of WS, have been recently reviewed [8][9][10][11][12]. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein and its cellular functions with the disease pathology. Molecular Genetics of Werner Syndrome (WS)WS is a rare autosomal recessive progeroid disorder characterized by the development of cataracts, changing of skin conditions, bird-like facies, atypical short stature, and premature graying or thinning of the hair [9]. Patients also often develop hypogonadism, osteoporosis, diabetes mellitus, artherosclerosis [13], and cancers, particularly sarcomas [14]. Onset of symptoms usually occurs in the third decade of life, and health subsequently declines with median age at death between 47-54 years [13]. Because WS presents with early-onset of conditions commonly seen in the aged, it is a good model system for the study of mechanisms of normal aging [15,16]. WRN BiochemistryThe causative factor of the majority of WS is mutation in the WRN gene, which codes for a member of the highly conserved RecQ family of helicases. While several different mutations within the gene are seen in WS, most result in production of truncated WRN protein [13]. 1Address correspondence to: Dr. Vilhelm A. Bohr, NIH Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224; BohrV@grc.nia.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the...

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…For instance, a deletion in WRN is found to be associated with higher mortality. The WRN gene encodes a RecQ DNA helicase involved in DNA replication and repair, transcription, and telomere maintenance (Rossi et al ., 2010). Deleterious mutations in this gene give rise to the premature aging syndrome Werner, and genetic variation in WRN has previously been associated with longevity (Soerensen et al ., 2012).…”

8p deletion is strongly linked to poor prognosis in breast cancer

“…41 The simultaneous involvement of at least 3 genes with a role for double strand break repair in case of 8p deletion would make those cancers particularly prone to development of such an "amplifier phenotype." 65 Several studies have suggested that cancers with a high degree of genomic instability might respond better to adjuvant radiation therapy or chemotherapy than genetically stable cancers. 68,69 It will thus be interesting to see if breast cancers with 8p-loss might respond better to neoadjuvant chemotherapy as compared to those lacking this alteration.…”

“…WRN it is a key regulator of fragile site stability 64 and involved in 2 major DNA repair pathways, the base excision repair (BER) and double strand break repair (DSBR) pathway. 65 In addition, POLB (8p11) and NAIL2 (8p23) are also involved in DNA repair as a key element in BER, and WRN likely acts cooperatively with POLB via its helicase and exonuclease activity. 66 It can be assumed that all these 3 interacting genes will be co-deleted in many cancers with 8p deletions.…”

Augmented cell death with Bloom syndrome helicase deficiency

“…There are five human RecQ-like proteins (RECQL1, BLM, WRN, RECQL4 and RECQ5), each having 3' to 5' DNA helicase activity, but little sequence similarity outside the helicase motifs (2,3). Three of these helicases (BLM, WRN and Rothmund-Thomson) show genomic instability and cancer susceptibility; however, each also has distinctive features (4,5).…”