Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40 DNA Replication through Replication Protein A Inactivation

Liu, Jen-Sing; Kuo, Shu-Ru; McHugh, Mary M.; Beerman, Terry A.; Melendy, Thomas

doi:10.1074/jbc.275.2.1391

Cited by 45 publications

(51 citation statements)

References 62 publications

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“…12,26 This interaction is disrupted by UV, adozelesin and cisplatin and a correlation between RPA-p53-binding and RPA2 phosphorylation status has been observed. 33,34 RPA2 has been shown to undergo cell cycle-dependent and damage-induced phosphorylation, and although the consequences of this phosphorylation are unclear, it may influence RPA conformation, DNA-binding characteristics, and/or its interactions with other proteins. 33,34 In conclusion, the widespread expression of RPA1 and RPA2 proteins in colon carcinomas suggests that these proteins are implicated in colon cancer growth.…”

Section: Discussionmentioning

confidence: 99%

“…33,34 RPA2 has been shown to undergo cell cycle-dependent and damage-induced phosphorylation, and although the consequences of this phosphorylation are unclear, it may influence RPA conformation, DNA-binding characteristics, and/or its interactions with other proteins. 33,34 In conclusion, the widespread expression of RPA1 and RPA2 proteins in colon carcinomas suggests that these proteins are implicated in colon cancer growth. Moreover, their association with advanced stage, lymph node metastasis as well as their increased expression in metastatic sites supports a role in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

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Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

et al. 2007

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Replication protein A (RPA), a component of the origin recognition complex, is required for stabilization of single-stranded DNA at early and later stages of DNA replication being thus critical for eukaryotic DNA replication. Experimental studies in colon cancer cell lines have shown that RPA protein may be the target of cytotoxins designed to inhibit cellular proliferation. This is the first study to investigate the expression of RPA1 and RPA2 subunits of RPA protein and assess their prognostic value in colon cancer patients. We analyzed immunohistochemically the expression of RPA1 and RPA2 proteins in a series of 130 colon cancer resection specimens in relation to conventional clinicopathological parameters and patients' survival. Statistical significant positive associations emerged between: (a) RPA1 and RPA2 protein expressions (P ¼ 0.0001), (b) RPA1 and RPA2 labelling indices (LIs) and advanced stage of the disease (P ¼ 0.001 and 0.003, respectively), (c) RPA1 and RPA2 LIs and the presence of lymph node metastasis (P ¼ 0.002 and 0.004, respectively), (d) RPA1 LI and the number of infiltrated lymph nodes (P ¼ 0.021), (e) RPA2 LI and histological grade of carcinomas (P ¼ 0.05). Moreover, a statistical significant higher RPA1 LI was observed in the metastatic sites compared to the original ones (P ¼ 0.012). RPA1 and RPA2 protein expression associated with adverse patients' outcome in both univariate (log rank test: Po0.00001 and 0.00001, respectively) and multivariate (Cox model: P ¼ 0.092 and 0.0001, respectively) statistical analysis. Statistical significant differences according to the expression of RPA1 and RPA2 proteins were also noticed in the survival of stage II (Po0.00001 and 0.0016, respectively) and stage III (P ¼ 0.0029 and 0.0079, respectively) patients. In conclusion, RPA1 and RPA2 proteins appear to be useful prognostic indicators in colon cancer patients and attractive therapeutic targets for regulation by tumor suppressors or other proteins involved in the control of cell proliferation. Modern Pathology (2007) 20, 159-166.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

et al. 2007

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“…To date, several anti-cancer drugs have been identified that interact with the RPA complex (Liu et al, 2000;Peters et al, 2001). One of these, tirapazamine, is a hypoxia-activated cytotoxic agent which is currently in phase III clinical studies and has been localized to RPA2 (Peters et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of replication protein A2 (RPA2) from Cryptosporidium parvum

2004

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Replication protein A (RPA) is a heterotrimeric complex of single-stranded DNA-binding proteins that play multiple roles in eukaryotic DNA metabolism. The RPA complex is typically composed of heterologous proteins (termed RPA1, RPA2 and RPA3) in animals, plants and fungi, which possess different functions. Previously, two distinct, short-type RPA large subunits (CpRPA1 and CpRPA1B) from the apicomplexan parasite Cryptosporidium parvum were characterized. Here are reported the identification and characterization of a putative middle RPA subunit (CpRPA2) from this unicellular organism. Although the CpRPA2 gene encodes a predicted 40?1 kDa peptide, which is larger than other RPA2 subunits characterized to date, Western blot analysis of oocyst preparations detected a native CpRPA2 protein with a molecular mass of approximately 32 kDa, suggesting that CpRPA2 might undergo post-translational cleavage or the gene was translated at an alternative start codon. Immunofluorescence microscopy using a rabbit anti-CpRPA2 antibody revealed that CpRPA2 protein was mainly distributed in the cytosol (rather than the nuclei) of C. parvum sporozoites. Semi-quantitative RT-PCR data indicated that CpRPA2 was differentially expressed in a tissue culture model with highest expression in intracellular parasites infecting HCT-8 cells for 36 and 60 h. Sequence comparison suggests that RPA2 is a group of poorly conserved proteins. Nonetheless, functional analyses of recombinant proteins confirmed that CpRPA2 is a single-stranded DNA-binding protein and that it could serve as an in vitro phosphorylation target by a DNA-dependent protein kinase. The minimal length of poly(dT) required for CpRPA2 binding is 17 nucleotides, and the DNA-binding capability was inhibited by phosphorylation in vitro. These observations provide additional evidence on the divergence of RPA proteins between C. parvum and host, implying that the parasite DNA replication machinery could be explored as a chemotherapeutic target.

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“…Because RPA levels were similar in extracts of heated and non-heated cells and because RPA was relatively resistant to direct heat inactivation, we proposed that the observed response reflected the activation of a checkpoint that targeted and inactivated RPA. A regulatory role for RPA in DNA replication has also been suggested in cells exposed to ionizing radiation (31)(32)(33)(34)(35).…”

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Regulation of DNA Replication after Heat Shock by Replication Protein A-Nucleolin Interactions

Wang

Guan

Wang

et al. 2001

Journal of Biological Chemistry

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Heat shock inhibits replicative DNA synthesis, but the underlying mechanism remains unknown. We investigated mechanistic aspects of this regulation in melanoma cells using a simian virus 40 (SV40)-based in vitro DNA replication assay. Heat shock (44°C) caused a monotonic inhibition of cellular DNA replication following exposures for 5-90 min. SV40 DNA replication activity in extracts of similarly heated cells also decreased after 5-30 min of exposure, but returned to near control levels after 60 -90 min of exposure. This transient inhibition of SV40 DNA replication was eliminated by recombinant replication protein A (rRPA), suggesting a regulatory process targeting this key DNA replication factor. SV40 DNA replication inhibition was associated with a transient increase in the interaction between nucleolin and RPA that peaked at 20 -30 min. Because binding to nucleolin compromises the ability of RPA to support SV40 DNA replication, we suggest that the observed interaction reflects a mechanism whereby DNA replication is regulated after heat shock. The relevance of this interaction to the regulation of cellular DNA replication is indicated by the transient translocation in heated cells of nucleolin from the nucleolus into the nucleoplasm with kinetics very similar to those of SV40 DNA replication inhibition and of RPA-nucleolin interaction. Because the targeting of RPA by nucleolin in heated cells occurs in an environment that preserves the activity of several essential DNA replication factors, active processes may contribute to DNA replication inhibition to a larger degree than presently thought. RPAnucleolin interactions may reflect an early step in the regulation of DNA replication, as nucleolin relocalized into the nucleolus 1-2 h after heat exposure but cellular DNA replication remained inhibited for up to 8 h. We propose that the nucleolus functions as a heat sensor that uses nucleolin as a signaling molecule to initiate inhibitory responses equivalent to a checkpoint.DNA replication is at the center of the eukaryotic cell cycle, and its regulation under conditions of stress, or after exposure to DNA-damaging agents, is under the control of intricate pathways that are only now beginning to be characterized. Although the mechanisms regulating DNA replication after DNA damage are studied intensively and a considerable amount of information is now available (reviewed in Ref.

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Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40 DNA Replication through Replication Protein A Inactivation

Cited by 45 publications

References 62 publications

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

Functional characterization of replication protein A2 (RPA2) from Cryptosporidium parvum

Regulation of DNA Replication after Heat Shock by Replication Protein A-Nucleolin Interactions

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