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2004. Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8
- J. Virol
"... In this study, we have used immunoprecipitation and mass spectrometry to identify over 50 cellular and viral proteins that are associated with the herpes simplex virus 1 (HSV-1) ICP8 single-stranded DNA-binding protein. Many of the coprecipitating cellular proteins are known members of large cellula ..."
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Cited by 55 (2 self)
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In this study, we have used immunoprecipitation and mass spectrometry to identify over 50 cellular and viral proteins that are associated with the herpes simplex virus 1 (HSV-1) ICP8 single-stranded DNA-binding protein. Many of the coprecipitating cellular proteins are known members of large cellular complexes involved in (i) DNA replication or damage repair, including RPA and MSH6; (ii) nonhomologous and homologous recombination, including the catalytic subunit of the DNA-dependent protein kinase, Ku86, and Rad50; and (iii) chromatin remodeling, including BRG1, BRM, hSNF2H, BAF155, mSin3a, and histone deacetylase 2. It appears that DNA mediates the association of certain proteins with ICP8, while more direct protein-protein interactions mediate the association with other proteins. A number of these proteins accumulate in viral replication compartments in the infected cell nucleus, indicating that these proteins may have a role in viral replication. WRN, which functions in cellular recombination pathways via its helicase and exonuclease activ-ities, is not absolutely required for viral replication, as viral yields are only very slightly, if at all, decreased in WRN-deficient human primary fibroblasts compared to control cells. In Ku70-deficient murine embryonic fibroblasts, viral yields are increased by almost 50-fold, suggesting that the cellular nonhomologous end-joining pathway inhibits HSV replication. We hypothesize that some of the proteins coprecipitating with ICP8 are involved in HSV replication and may give new insight into viral replication mechanisms.
Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res
, 2004
"... The transient opening and closing of tumor vasculature result in periods of severe oxygen deprivation (hypoxia) followed by reoxygenation. This exerts a positive selective pressure for cells that have lost their sensitivity to killing by reduced oxygen levels. These cells are effectively resistant t ..."
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Cited by 10 (2 self)
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The transient opening and closing of tumor vasculature result in periods of severe oxygen deprivation (hypoxia) followed by reoxygenation. This exerts a positive selective pressure for cells that have lost their sensitivity to killing by reduced oxygen levels. These cells are effectively resistant to hypoxia-induced apoptosis and conventional therapeutic approaches. Here we show hypoxia-induced S-phase arrest results in regions of single-stranded DNA in stalled replication forks and signals the activation of ATR. S-phase cells represent the most sensitive phase of the cell cycle to the stress of hypoxia/reoxygenation. Loss of ATR or inhibition of ATR kinase activity results in a further loss of reproductive viability in S-phase cells when exposed to hypoxic conditions followed by reoxygenation but has little effect on the inhibition of DNA synthesis. This is, at least in part, mediated via Chk1 signaling because loss of Chk1 also results in increased sensitivity to hypoxia/reoxygenation. The observed decrease
Rad50 depletion impacts upon ATR-dependent DNA damage responses
- Hum. Mol. Genet
, 2005
"... The Mre11/Rad50/NBS1 (MRN) complex is mutated in inherited genomic instability syndromes featuring cancer predisposition, mental retardation and immunodeficiency. It functions both in DNA double-strand break repair and in controlling the ataxia telangiectasia mutated (ATM) kinase during the response ..."
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Cited by 8 (0 self)
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The Mre11/Rad50/NBS1 (MRN) complex is mutated in inherited genomic instability syndromes featuring cancer predisposition, mental retardation and immunodeficiency. It functions both in DNA double-strand break repair and in controlling the ataxia telangiectasia mutated (ATM) kinase during the response to these lesions. Patients inheriting homozygosity for an NBS1 hypomorphic allele display reduced phospho-rylation of signaling factors such as Chk1, but not of chromatin-associated factor H2AX, after stresses that activate the ATM-related kinase, ATR. Therefore, we tested whether MRN has a global controlling role over the ATR kinase through the study of MRN deficiencies generated via RNA interference. We show for the first time that MRN is required for ATR-dependent phosphorylation of structural maintenance of chromo-somes 1 (Smc1), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. We have uncovered novel phenotypes caused by MRN deficiency that support a func-tional link between this complex, ATR and Smc1, including hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint and a specific pattern of genomic instability. In addition, certain ATR-dependent responses do not require MRN. These studies demonstrate that there is indeed a controlling role for MRN over the ATR kinase and have established that the downstream events under this control are broad, including both chromatin-associated and diffuse signaling factors, but may not be universal. These studies contribute to our understanding of the central role that MRN plays in damage detection and signaling, which serve to maintain genomic stability and resist neoplastic transformation.
MRE11 complex links RECQ5 helicase to sites of DNA damage
, 2008
"... RECQ5 DNA helicase suppresses homologous recombination (HR) possibly through disruption of RAD51 filaments. Here, we show that RECQ5 is con-stitutively associated with the MRE11–RAD50–NBS1 (MRN) complex, a primary sensor of DNA double-strand breaks (DSBs) that promotes DSB repair and regulates DNA d ..."
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Cited by 7 (1 self)
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RECQ5 DNA helicase suppresses homologous recombination (HR) possibly through disruption of RAD51 filaments. Here, we show that RECQ5 is con-stitutively associated with the MRE11–RAD50–NBS1 (MRN) complex, a primary sensor of DNA double-strand breaks (DSBs) that promotes DSB repair and regulates DNA damage signaling via activation of the ATM kinase. Experiments with purified pro-teins indicated that RECQ5 interacts with the MRN complex through both MRE11 and NBS1. Functional assays revealed that RECQ5 specifically inhibited the 3’!5 ’ exonuclease activity of MRE11, while MRN had no effect on the helicase activity of RECQ5. At the cellular level, we observed that the MRN complex was required for the recruitment of RECQ5 to sites of DNA damage. Accumulation of RECQ5at DSBs was neither dependent on MDC1 that mediates binding of MRN to DSB-flanking chro-matin nor on CtIP that acts in conjunction with MRN to promote resection of DSBs for repair by HR. Collectively, these data suggest that the MRN complex recruits RECQ5 to sites of DNA damage to regulate DNA repair.
Rad50 Is Dispensable for the Maintenance and Viability of Postmitotic Tissues � †
, 2008
"... This article cites 63 articles, 28 of which can be accessed free ..."
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Cited by 5 (2 self)
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This article cites 63 articles, 28 of which can be accessed free
Active Role for Nibrin in the Kinetics of Atm Activation
, 2005
"... This article cites 46 articles, 25 of which can be accessed free ..."
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Cited by 5 (0 self)
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This article cites 46 articles, 25 of which can be accessed free
Analysis of DNA double-strand break response
, 2010
"... and chromatin structure in mitosis using laser microirradiation ..."
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Cited by 2 (1 self)
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and chromatin structure in mitosis using laser microirradiation
and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull
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Me
, 2016
"... All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. ..."
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All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
Me
, 2016
"... All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. ..."
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All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
