Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes

Weirich‐Schwaiger, Helga; Weirich, Harald G.; Gruber, Bernhard; Schweiger, Manfred; Hirsch-Kauffman, M.

doi:10.1016/0921-8734(94)90006-x

Cited by 105 publications

(41 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the absence of WRN (i.e., WS cells), although PARP-1 is still able to sense the DNA damage, as detected by the auto-poly(ADPribosyl)ation modification, the subsequent modification of target proteins is strongly impaired. A logical consequence of this lack of signal transmission may be the accumulation of DNA damage or a delay in the repair process, leading to a premature senescence caused by a diminished DNA repair capacity, as was previously proposed for primary cells from WS and Cockayne syndrome patients (50). Interestingly, there is evidence that longevity is associated with a high poly(ADP-ribosyl)ation capacity (16,28), and our data with WS cells support this hypothesis.…”

Section: Discussionsupporting

confidence: 78%

Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

Kobbe

Harrigan

May

et al. 2003

Molecular and Cellular Biology

135

120

View full text Add to dashboard Cite

A defect in the Werner syndrome protein (WRN) leads to the premature aging disease Werner syndrome (WS). Hallmark features of cells derived from WS patients include genomic instability and hypersensitivity to certain DNA-damaging agents. WRN contains a highly conserved region, the RecQ conserved domain, that plays a central role in protein interactions. We searched for proteins that bound to this region, and the most prominent direct interaction was with poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme that protects the genome by responding to DNA damage and facilitating DNA repair. In pursuit of a functional interaction between WRN and PARP-1, we found that WS cells are deficient in the poly(ADP-ribosyl)ation pathway after they are treated with the DNA-damaging agents H 2 O 2 and methyl methanesulfonate. After cellular stress, PARP-1 itself becomes activated, but the poly(ADP-ribosyl)ation of other cellular proteins is severely impaired in WS cells. Overexpression of the PARP-1 binding domain of WRN strongly inhibits the poly(ADP-ribosyl)ation activity in H 2 O 2 -treated control cell lines. These results indicate that the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway.Werner syndrome (WS) is a rare autosomal recessive disorder characterized by premature aging and the early onset of cancer (26). WS is caused by mutations in the gene (WRN) encoding the Werner syndrome protein (WRN) (51). WRN is a multifunctional protein which possesses three catalytic activities, which reside in the amino terminus (3Ј-5Ј exonuclease) and the central part of the protein (DNA-dependent ATPase and 3Ј-5Ј helicase) (5). The RecQ conserved (RQC) motif resides in the C-terminal part of WRN and is present in almost all of the RecQ family members (51). Recently, we have shown that a region of 144 amino acids (aa) of the RQC domain binds to and stimulates flap endonuclease 1 (FEN-1) (7), binds to the Bloom's syndrome protein (49) and telomere repeat binding factor 2 (30), and contains a nuclear localization signal-dependent nucleolar targeting sequence (48). Thus, the highly conserved RQC domain of WRN appears to play a very important role in mediating WRN protein interactions and in regulating the nuclear trafficking (nucleolar targeting) of the protein. In an effort to better understand the functional role(s) of this domain, we performed a series of pull-down experiments to identify proteins that specifically bind to the WRN RQC domain. The most prominent binder that we identified was poly-(ADP-ribose) polymerase 1 (PARP-1), whose binding represents a novel protein interaction with WRN.PARP-1 is a nuclear enzyme belonging to the DNA damage surveillance network. The protein responds to DNA damage by transferring 50 to 200 molecules of ADP-ribose to various nuclear proteins, including transcription factors, histones, and PARP-1 itself (8). This poly(ADP-ribosyl)ation activity of PARP-1 appears to be...

show abstract

Section: Discussionsupporting

confidence: 78%

Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

Kobbe

Harrigan

May

et al. 2003

Molecular and Cellular Biology

135

120

View full text Add to dashboard Cite

show abstract

“…The use of MN as biomarkers is based on the fact that cancer cells present cytogenetic abnormalities, which reinforces the hypothesis that chromosomal damages are directly involved in cancer etiology [50].…”

Section: Discussionmentioning

confidence: 83%

Genotoxic effects of anesthetics in operating room personnel evaluated by micronucleus test

Araujo¹,

Silva-Grecco²,

Bisinotto³

et al. 2013

J Anesthesiol Clin Sci

View full text Add to dashboard Cite

Exposure to certain chemical agents causes damage to the genetic material. There is controversy about the genotoxic and/or mutagenic effect caused by acute or chronic anesthetics exposure. The aim of this research was to assess and compare the frequency of micronuclei (MN) in professionals working in operating rooms and other hospital areas. The genotoxic and cytotoxic effects were evaluated in lymphocytes using the micronucleus test and the proliferative index, respectively. We examined peripheral blood lymphocyte cultures from 30 operating room professionals (exposed group) and 30 professionals non-exposed in other hospital areas of the same hospital (control group). There was no statistically significant difference in proliferative index between the groups. Nevertheless, there was an increase in MN frequency in binucleated (BN) cells in the exposed group (p=0.0003) compared to the control group. Moreover, there was a statistically significant difference between genders (p=0.0187), and the frequency of MN in BN cells from women was higher than in men. Therefore, gender influenced the frequency of MN. The age and period of working time in an operating room influenced the MN frequency only in women professionals. Thereby, there was a genotoxic effect in occupationally exposed professionals, and the micronucleus test could be used in the biomonitoring of human populations for evaluating the risk of developing cancer.

show abstract

“…UV-induced DNA damage is repaired by NER. WS cells may possess more proficient UV repair capacity than cells from old donors, both in telomeric regions (Kruk et al, 1995) and overall genomic repair (Weirich-Schwaiger et al, 1994). WS cells have normal recovery of RNA synthesis after UV irradiation and in primary WS fibroblasts genespecific repair of UV-induced damage is normal (Webb et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes

Cited by 105 publications

References 32 publications

Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

Genotoxic effects of anesthetics in operating room personnel evaluated by micronucleus test

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

Contact Info

Product

Resources

About