Werner syndrome ( WRN ) gene variants and their association with altered function and age-associated diseases

Lebel, Michel; Monnat, Raymond J.

doi:10.1016/j.arr.2017.11.003

Cited by 40 publications

(34 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There was no further increase in epithelial proliferation in N/Tert-1+HPV16 cells in the absence of WRN. Werner syndrome patients suffer from progeria but are also predisposed to certain cancers; therefore, WRN is a tumor suppressor protein ( 31 , 54 , 55 ). The thickening of the N/Tert-1 epithelium in the absence of WRN is a proliferative signal, a hallmark of the absence of a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

James

Das

Morgan

et al. 2020

mSphere

View full text Add to dashboard Cite

Human papillomaviruses recruit a host of DNA damage response factors to their viral genome to facilitate homologous recombination replication in association with the viral replication factors E1 and E2. We previously demonstrated that SIRT1 deacetylation of WRN promotes recruitment of WRN to E1-E2 replicating DNA and that WRN regulates both the levels and fidelity of E1-E2 replication. The deacetylation of WRN by SIRT1 results in an active protein able to complex with replicating DNA, but a protein that is less stable. Here, we demonstrate an inverse correlation between SIRT1 and WRN in CIN cervical lesions compared to normal control tissue, supporting our model of SIRT1 deacetylation destabilizing WRN protein. We CRISPR/Cas9 edited N/Tert-1 and N/Tert-1+HPV16 cells to knock out WRN protein expression and subjected the cells to organotypic raft cultures. In N/Tert-1 cells without WRN expression, there was enhanced basal cell proliferation, DNA damage, and thickening of the differentiated epithelium. In N/Tert-1+HPV16 cells, there was enhanced basal cell proliferation, increased DNA damage throughout the epithelium, and increased viral DNA replication. Overall, the results demonstrate that the expression of WRN is required to control the proliferation of N/Tert-1 cells and controls the HPV16 life cycle in these cells. This complements our previous data demonstrating that WRN controls the levels and fidelity of HPV16 E1-E2 DNA replication. The results describe a new role for WRN, a tumor suppressor, in controlling keratinocyte differentiation and the HPV16 life cycle. IMPORTANCE HPV16 is the major human viral carcinogen, responsible for around 3 to 4% of all cancers worldwide. Our understanding of how the viral replication machinery interacts with host factors to control/activate the DNA damage response to promote the viral life cycle remains incomplete. Recently, we demonstrated a SIRT1-WRN axis that controls HPV16 replication, and here we demonstrate that this axis persists in clinical cervical lesions induced by HPV16. Here, we describe the effects of WRN depletion on cellular differentiation with or without HPV16; WRN depletion results in enhanced proliferation and DNA damage irrespective of HPV16 status. Also, WRN is a restriction factor for the viral life cycle since replication is disrupted in the absence of WRN. Future studies will focus on enhancing our understanding of how WRN regulates viral replication. Our goal is to ultimately identify cellular factors essential for HPV16 replication that can be targeted for therapeutic gain.

show abstract

Section: Discussionmentioning

confidence: 99%

Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

James

Das

Morgan

et al. 2020

mSphere

View full text Add to dashboard Cite

show abstract

“…(2) In long replication blocks (>24 h) resulting in fork collapse, new origins are fired in an attempt to compensate, and repair takes place by remodelling, utilizing structure‐specific endonuclease complexes* that generate DSBs, promoting Rad51‐dependent homologous recombination (Figure ). The significance of the above factors is underscored by the severity of the clinical manifestations presented in disorders such as Bloom* and Werner* syndromes, in which corresponding helicases are mutated .…”

Section: Ddr–pdr: An Integrated Genome–proteome Maintenance Networkmentioning

confidence: 99%

Integrating the DNA damage and protein stress responses during cancer development and treatment

Gorgoulis

Pefani

Pateras

et al. 2018

The Journal of Pathology

105

View full text Add to dashboard Cite

During evolution, cells have developed a wide spectrum of stress response modules to ensure homeostasis. The genome and proteome damage response pathways constitute the pillars of this interwoven ‘defensive’ network. Consequently, the deregulation of these pathways correlates with ageing and various pathophysiological states, including cancer. In the present review, we highlight: (1) the structure of the genome and proteome damage response pathways; (2) their functional crosstalk; and (3) the conditions under which they predispose to cancer. Within this context, we emphasize the role of oncogene‐induced DNA damage as a driving force that shapes the cellular landscape for the emergence of the various hallmarks of cancer. We also discuss potential means to exploit key cancer‐related alterations of the genome and proteome damage response pathways in order to develop novel efficient therapeutic modalities. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

show abstract

“…However, due to the premature death of WS patients and the limited number of cases in the WS registry, the prevalence of clinical features resembling early Alzheimer's Disease or dementia in some WS patients cannot be excluded. See [335] for a recent discussion of WS and the central nervous system. A clinical feature that distinguishes WS from BS is that cancer types in WS are less broad than in BS.…”

Section: Werner Syndromementioning

confidence: 99%

History of DNA Helicases

Brosh

Matson

2020

Genes

View full text Add to dashboard Cite

Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970’s to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field – where it has been, its current state, and where it is headed.

show abstract

Werner syndrome ( WRN ) gene variants and their association with altered function and age-associated diseases

Cited by 40 publications

References 132 publications

Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

Integrating the DNA damage and protein stress responses during cancer development and treatment

History of DNA Helicases

Contact Info

Product

Resources

About