Helicases and aging

Nakura, Jun; Ye, L; Morishima, Atsuyuki; Kohara, Katsuhiko; Miki, Tetsuro

doi:10.1007/s000180050036

Cited by 39 publications

(22 citation statements)

References 104 publications

(114 reference statements)

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“…It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression (6), and our results suggest that the same is the case for normal aging. The transcription process requires unwinding of the DNA duplex, and involvement of helicases in transcription is exemplified by the observation that one of the basal transcription factors, TFIIH, exhibits DNA unwinding activity (38).…”

Section: Discussionsupporting

confidence: 75%

“…The transcription process requires unwinding of the DNA duplex, and involvement of helicases in transcription is exemplified by the observation that one of the basal transcription factors, TFIIH, exhibits DNA unwinding activity (38). In addition to WS, six other segmental progeroid syndromes are caused by mutations in helicase genes, which implies contribution of aberrant helicases to phenotypes in normal aging (6). One of these is Cockayne syndrome (CS), in which we have demonstrated a transcription defect after hydrogen peroxide exposure (10).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which the biochemical deficiencies resulting from WRN mutations lead to the characteristic pathology of the syndrome are not yet understood. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression (6) and that a transcription defect may be crucial to the development of the syndrome (7). Increasing evidence suggests that WRN has a role in transcription.…”

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confidence: 99%

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Gene expression profiling in Werner syndrome closely resembles that of normal aging

Kyng

May

Kølvraa

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

135

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Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.W erner syndrome (WS) is an autosomal recessive disease characterized by early onset of many signs of normal aging, such as graying of the hair, scleroderma-like skin changes, ocular cataracts, diabetes, degenerative vascular disease, osteoporosis, and high incidence of some types of cancers (1). As a segmental progeroid syndrome, WS does not exhibit all of the features of normal aging but nevertheless is a very useful model system for the molecular study of normal aging.The molecular basis of WS is a single mutation in the WRN gene, resulting in a truncated WS protein (WRN) characterized by a loss of nuclear localization signal and protein function (2). WRN has been demonstrated to possess helicase and exonuclease activities (3, 4) and belongs to the RecQ family of helicases. Various defects in DNA replication, recombination, repair, and transcription are found in WS fibroblasts (reviewed in ref. 5). The mechanisms by which the biochemical deficiencies resulting from WRN mutations lead to the characteristic pathology of the syndrome are not yet understood. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression (6) and that a transcription defect may be crucial to the development of the syndrome (7). Increasing evidence suggests that WRN has a role in transcription. Human WRN activates transcription in a yeast system (8), and recent studies from this laboratory demonstrated that RNA polymerase (pol) II transcription is reduced by 40-60% in WS cells, indicating a primary defect in transcription (7). Supporting this finding, we found that RNA pol II transcription i...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Gene expression profiling in Werner syndrome closely resembles that of normal aging

Kyng

May

Kølvraa

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

135

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“…Among the human RECQ helicases, BLM and WRN were shown to be the determinants of the Bloom and Werner syndrome, respectively (32,33), and two kindreds with Rothmund-Thomson syndrome were shown to segregate with mutations in RECQ4 (34). These RecQ helicase syndromes have been reported to exhibit genetic instability, and one of the clinical manifestations of Werner and Rothmund-Thomson syndromes patients is premature aging (35)(36)(37). Interestingly, sgs1 nulls also appear to exhibit a reduced lifespan, defined for the budding yeast as the total number of buds a mother cell can produce (38).…”

mentioning

confidence: 99%

Mice lacking DNA topoisomerase IIIβ develop to maturity but show a reduced mean lifespan

Kwan

Wang

2001

Proc. Natl. Acad. Sci. U.S.A.

107

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Targeted gene disruption in the murine TOP3␤ gene-encoding DNA topoisomerase III␤ was carried out. In contrast to the embryonic lethality of mutant mice lacking DNA topoisomerase III␣, top3␤ ؊͞؊ nulls are viable and grow to maturity with no apparent defects. Mice lacking DNA topoisomerase III␤ have a shorter life expectancy than their wild-type littermates, however. The mean lifespan of the top3␤ ؊͞؊ mice is about 15 months, whereas that of their wild-type littermates is longer than 2 years. Mortality of the top3␤ ؊͞؊ nulls appears to correlate with lesions in multiple organs, including hypertrophy of the spleen and submandibular lymph nodes, glomerulonephritis, and perivascular infiltrates in various organs. Because the DNA topoisomerase III isozymes are likely to interact with helicases of the RecQ family, enzymes that include the determinants of human Bloom, Werner, and Rothmund-Thomson syndromes, the shortened lifespan of top3␤ ؊͞؊ mice points to the possibility that the DNA topoisomerase III isozymes might be involved in the pathogenesis of progeroid syndromes caused by defective RecQ helicases.RecQ helicases ͉ human progeroid syndromes I n human as well as in mouse, DNA topoisomerase III␤ is the newest member of the DNA topoisomerase family (1, 2). It belongs to the type IA subfamily of DNA topoisomerases that are characterized by their transient breakage of a DNA strand by transesterification between an enzyme tyrosyl group and a DNA 5Ј phosphoryl group (3, 4). The type IA enzymes also display a strong specificity for negatively supercoiled DNA and DNA containing single-stranded regions (3, 4). Biochemically, mammalian DNA topoisomerase III␤ resembles mammalian DNA topoisomerase III␣ as well as bacterial and yeast DNA topoisomerase III (2).Information on the cellular functions of the type IA enzymes mostly is derived from studies of bacteria and yeasts. In bacteria, there are two type IA enzymes, DNA topoisomerases I and III. The major role of bacterial DNA topoisomerase I, encoded by the topA gene, appears to be the prevention of excessive negative supercoiling of intracellular DNA (3-5). The lethality resulting from inactivating Escherichia coli DNA topoisomerase I, for example, can be alleviated by mutations that reduce the cellular level of DNA gyrase (6-8), an enzyme that catalyzes DNAnegative supercoiling, or by the expression of eukaryotic or vaccinia virus DNA topoisomerase I (9, 10), a type IB enzyme that relaxes positively or negatively supercoiled DNA but is structurally and mechanistically very different from the type IA enzymes (3). The prominent role of E. coli DNA topoisomerase I in the removal of negative supercoils indicates that the other type IA enzyme in E. coli, the topB-encoded DNA topoisomerase III, is ineffective in this role. Purified E. coli DNA topoisomerase III is proficient in linking or unlinking DNA single strands, but is inefficient in the relaxation of negatively supercoiled DNAs (11). The two type IA E. coli enzymes may share, however, an essential cellular function unrel...

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“…In accordance with this finding it has been suggested that several phenotyical aspects WS are secondary consequences of aberrant gene expression (Nakura et al, 2000). Gene expression is changed to adapt to cellular stress (Lee et al, 1995;Moradas-Ferreira and Costa, 2000;Volkert and Landini, 2001;Kyng et al, 2003a;Moggs and Orphanides, 2003), and this adaptation is likely to be affected in aging because of constant exposure to cellular stress.…”

Section: Introductionmentioning

confidence: 81%

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

et al. 2005

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The accumulation of DNA damage and mutations is considered a major cause of cancer and aging. While it is known that DNA damage can affect changes in gene expression, transcriptional regulation after DNA damage is poorly understood. We characterized the expression of 6912 genes in human primary fibroblasts after exposure to three different kinds of cellular stress that introduces DNA damage: 4-nitroquinoline-1-oxide (4NQO), c-irradiation, or UV-irradiation. Each type of stress elicited damage specific gene expression changes of up to 10-fold. A total of 85 genes had similar changes in expression of 3-40-fold after all three kinds of stress. We examined transcription in cells from young and old individuals and from patients with Werner syndrome (WS), a segmental progeroid condition with a high incidence of cancer, and found various age-associated transcriptional changes depending upon the type of cellular stress. Compared to young individuals, both WS and old individuals had similarly aberrant transcriptional responses to c-and UV-irradiation, suggesting a role for Werner protein in stress-induced gene expression. Our results suggest that aberrant DNA damage-induced gene regulation may contribute to the aging process and the premature aging in WS.

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Helicases and aging

Cited by 39 publications

References 104 publications

Gene expression profiling in Werner syndrome closely resembles that of normal aging

Gene expression profiling in Werner syndrome closely resembles that of normal aging

Mice lacking DNA topoisomerase IIIβ develop to maturity but show a reduced mean lifespan

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

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