Cellular Deficiency of Werner Syndrome Protein or RECQ1 Promotes Genotoxic Potential of Hydroquinone and Benzo[a]pyrene Exposure

Garige, Mamatha; Sharma, Sudha

doi:10.1177/1091581814547422

Cited by 5 publications

(3 citation statements)

References 47 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As compared to control untreated U2OS cells, RECQ1 mRNA was also upregulated following treatment with chemotherapeutics 5-fluoro uracil (5-FU), gemcitabine, camptothecin as well as the laboratory carcinogen methylnitronitrosoguanidine (MNNG) and environmental mutagen benzo[a]pyrene ( Supplementary Figure 4 ). This is consistent with previous studies where RECQ1-depletion increased cellular sensitivity to camptothecin and benzo[a]pyrene [ 22 , 49 ].…”

Section: Resultssupporting

confidence: 93%

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

Parvathaneni

Chaudhary

et al. 2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

Sensitivity of cancer cells to DNA damaging chemotherapeutics is determined by DNA repair processes. Consequently, cancer cells may upregulate the expression of certain DNA repair genes as a mechanism to promote chemoresistance. Here, we report that RECQ1, a breast cancer susceptibility gene that encodes the most abundant RecQ helicase in humans, is a p53-regulated gene, potentially acting as a defense against DNA damaging agents. We show that RECQ1 mRNA and protein levels are upregulated upon treatment of cancer cells with a variety of DNA damaging agents including the DNA-alkylating agent methylmethanesulfonate (MMS). The MMS-induced upregulation of RECQ1 expression is p53-dependent as it was observed in p53-proficient but not in isogenic p53-deficient cells. The RECQ1 promoter is bound by endogenous p53 and is responsive to p53 in luciferase reporter assays suggesting that RECQ1 is a direct target of p53. Treatment with the chemotherapeutic drugs temozolomide and fotemustine also increased RECQ1 mRNA levels whereas depletion of RECQ1 enhanced cellular sensitivity to these agents. These results identify a previously unrecognized p53-mediated upregulation of RECQ1 expression in response to DNA damage and implicate RECQ1 in the repair of DNA lesions including those induced by alkylating and other chemotherapeutic agents.

show abstract

Section: Resultssupporting

confidence: 93%

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

Parvathaneni

Chaudhary

et al. 2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, haplotypic analyses on different WRN coding SNPs indicated that Chinese workers exposed to benzene were more at risk of developing hematotoxicity depending on their polymorphic amino acids at both positions 1074 and 1367 [ 31 , 32 ]. Indeed, it has been reported that WRN plays an important role in the protection of cells against the toxicity of benzene metabolites [ 47 – 49 ]. Thus, the difference between the polymorphic WRN variants in the population is likely due to how each variant interacts with their nuclear partners in cells and how efficient the different enzymatic activities of the WRN containing complexes are performing in cells.…”

Section: Discussionmentioning

confidence: 99%

Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities

et al. 2016

View full text Add to dashboard Cite

Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication and repair. Here, we present the results of a large-scale proteome analysis that has been undertaken to determine protein partners of different polymorphic WRN proteins found with relatively high prevalence in the human population. We expressed different fluorescently tagged-WRN (eYFP-WRN) variants in human 293 embryonic kidney cells (HEK293) and used a combination of affinity-purification and mass spectrometry to identify different compositions of WRN-associated protein complexes. We found that a WRN variant containing a phenylalanine residue at position 1074 and an arginine at position 1367 (eYFP-WRN(F-R)) possesses more affinity for DNA-PKc, KU86, KU70, and PARP1 than a variant containing a leucine at position 1074 and a cysteine at position 1367 (eYFP-WRN(L-C)). Such results were confirmed in a WRN-deficient background using WS fibroblasts. Interestingly, the exonuclase activity of WRN recovered from immunoprecipitated eYFP-WRN(L-C) variant was lower than the eYFP-WRN(F-R) in WS cells. Finally, HEK293 cells and WS fibroblasts overexpressing the eYFP-WRN(F-R) variant were more resistant to the benzene metabolite hydroquinone than cells expressing the eYFP-WRN(L-C) variant. These results indicate that the protein-protein interaction landscape of WRN is subject to modulation by polymorphic amino acids, a characteristic associated with distinctive cell survival outcome.

show abstract

“…Using the mouse model system, provided an indirect evidence for the DNA repair role for RecQL1 in the suppression of chromosome instability. Human cervical cancer cells deficient either in WRN or in RecQL1 were shown to be hypersensitive to hydroquinone and benzo(a) pyrene exposure indicating the participation of both WRN and RecQL1 proteins in the DSB repair pathway [Garige and Sharma, 2014]. Similar to RecQL1, RecQL5 also participates in DNA DSB repair [Schwendener et al, 2010;Maruyama et al, 2012;Paliwal et al, 2014], and the recruitment of RecQL5 to the sites of DNA DSBs depends on its interaction with a primary DSB sensor complex of 3 proteins: MRE11, RAD50, and NBS1 [Zheng et al, 2009].…”

Section: Recql4 Protects Cancer Cells From Endogenous and Exogenous Dna Damagementioning

confidence: 99%

Human RecQL4 as a Novel Molecular Target for Cancer Therapy

Balajee¹

2021

Cytogenet Genome Res

View full text Add to dashboard Cite

Human RecQ helicases play diverse roles in the maintenance of genomic stability. Inactivating mutations in 3 of the 5 human RecQ helicases are responsible for the pathogenesis of Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), RAPADILINO, and Baller-Gerold syndrome (BGS). WS, BS, and RTS patients are at increased risk for developing many age-associated diseases including cancer. Mutations in RecQL1 and RecQL5 have not yet been associated with any human diseases so far. In terms of disease outcome, RecQL4 deserves special attention because mutations in RecQL4 result in 3 autosomal recessive syndromes (RTS type II, RAPADILINO, and BGS). RecQL4, like other human RecQ helicases, has been demonstrated to play a crucial role in the maintenance of genomic stability through participation in diverse DNA metabolic activities. Increased incidence of osteosarcoma in RecQL4-mutated RTS patients and elevated expression of RecQL4 in sporadic cancers including osteosarcoma suggest that loss or gain of RecQL4 expression is linked with cancer susceptibility. In this review, current and future perspectives are discussed on the potential use of RecQL4 as a novel cancer therapeutic target.

show abstract

Cellular Deficiency of Werner Syndrome Protein or RECQ1 Promotes Genotoxic Potential of Hydroquinone and Benzo[a]pyrene Exposure

Cited by 5 publications

References 47 publications

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities

Human RecQL4 as a Novel Molecular Target for Cancer Therapy

Contact Info

Product

Resources

About