Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

Kyng, Kasper Jacobsen; May, Alfred; Stevnsner, Tinna; Becker, Kevin G.; Kølvrå, Steen; Bohr, Vilhelm A.

doi:10.1038/sj.onc.1208692

Cited by 42 publications

(20 citation statements)

References 59 publications

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“…Gene expression profiling in WS closely resembles that of normal aging, suggesting that the transcription alterations common to WS and normal aging represent general events in the aging process [5]. Cells from WS and old individuals had similarly aberrant transcriptional responses to IR (ionizing radiation) and UV irradiation, suggesting a role for WRN in stress-induced gene expression [6]. The cellular studies clearly indicate that WS has multiple deficiencies and the WRN gene product is likely to have pleiotropic functions in vivo.…”

mentioning

confidence: 94%

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Sharma

Doherty

Brosh

2006

Biochemical Journal

239

264

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Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.Key words: aging, cancer, DNA repair, genomic instability, helicase, RecQ. INTRODUCTIONUnderstanding the molecular mechanisms of RecQ helicases is fundamental to deciphering the roles of these enzymes in cellular DNA metabolism. Since the discovery of Escherichia coli RecQ and its implicated role in genetic recombination, the world of RecQ helicases has become significantly more complex with the identification and characterization of a number of eukaryotic RecQ helicases that are important in the replicational stress response and maintenance of genomic stability.Classification of RecQ helicases and molecular-genetic analyses of their biochemical and cellular functions gained prominence with the understanding that certain rare genetic disorders [WS (Werner syndrome), BS (Bloom syndrome) and RTS (Rothmund-Thomson syndrome)] are a consequence of mutations in the human RecQ genes WRN, BLM and RECQ4 respectively. WS is characterized by premature aging with an elevated risk of age-associated diseases such as cancer, atherosclerotic cardiovascular disease, diabetes mellitus (Type II) and osteoporosis [1]. Epigenetic inactivation of WRN is detected in a number of human cancers [2]. BS is associated with a very high incidence of different types of cancers, both solid tumours and leukaemia, and also manifested by skin disorders, proportional dwarfism, immunodeficiency and male sterility [1]. People with RTS, also known as poikiloderma congenitale, displays growth deficiency, photosensitivity with poikilodermatous skin changes, early greying and hair loss, juvenile cataracts and a predisposition to malignancy, especially osteogenic sarcomas [1]. Apart from RTS, RECQ4 mutations were detected in Finnish patients with an autosomal recessive disorder RAPADILINO syndrome [radial hypoplasia/aplasia, patellae hypoplasia/aplasia and cleft or highly arched palate, diarrhoea and dislocated joints, little size (height at least 2 S.D. smaller than the average height) and limb malformation, nose slender and normal intelligence] [3]. Although many features o...

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mentioning

confidence: 94%

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Sharma

Doherty

Brosh

2006

Biochemical Journal

239

264

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“…These opposing actions have indicated that senescence is a 'double-edged sword', in that senescence acts as a tumor suppressor mechanism to directly prevent cancer, yet potentially enhances cancer via the action of senescent cell products (34). Prior studies have shown that WS cells have gene expression patterns that are characteristic of control senescent cells even when they are not actually senescent (35,36). We obtained suggestive but not definitive evidence that, as they reach crisis, tumor cells derived from WS fibroblasts may be more malignant than those from control fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts from Werner syndrome patients: Cancer cells derived by experimental introduction of oncogenes maintain malignant properties despite entering crisis

Hornsby¹

2009

Oncol Rep

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Abstract. Werner syndrome (WS) results from defects in the gene encoding WRN RecQ helicase. WS fibroblasts undergo premature senescence in culture. Because cellular senescence is a tumor suppressor mechanism, we examined whether WS fibroblasts exhibited reduced tumorigenicity, in comparison to control cells, in a model of experimental conversion of normal human cells to cancer cells. The combination of oncogenic Ras (Ha-Ras V12G ) and SV40 large T antigen (SV40 LT) causes human cells to acquire neoplastic properties in the absence of telomerase. We found that WS cells could also be converted to a tumorigenic state by these oncogenes, as evidenced by invasion and metastasis of cells implanted in immunodeficient mice. Ras/SV40 LT-expressing cells retained invasiveness and malignant properties even when cells reached crisis in tumors in vivo. High levels of gelatinase were found by an in situ assay in Ras/SV40 LT-expressing cells undergoing crisis. We conclude that, despite evidence of accelerated senescence in WS cells, there is no evidence that the absence of active WRN acts as a barrier to neoplastic transformation. Moreover, we find that tumorigenic human cells retain malignant properties of the cells as they approach and reach crisis.

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“…The phenotypic resemblance of WS to precocious aging has often begged the question of how closely WS is related to normal aging processes. Recent microarray studies have indicated that gene expression patterns are similar between WS cells and those from aged individuals after exposure to gamma and UV radiation, suggesting similarities in cellular microenvironments [41]. The diverse roles of WRN and the deleterious effects induced in its absence have prompted several groups to investigate whether allelic variants in WRN are associated with aging-related afflictions in the general population.…”

Section: Progeroid Syndromes Caused By Defects In Dna Helicases/dna Rmentioning

confidence: 99%

Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions

Ramírez

Cadiñanos

Varela

et al. 2006

Cell. Mol. Life Sci.

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Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.

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Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

Cited by 42 publications

References 59 publications

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Fibroblasts from Werner syndrome patients: Cancer cells derived by experimental introduction of oncogenes maintain malignant properties despite entering crisis

Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions

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