Involvement of DNA-dependent Protein Kinase in UV-induced Replication Arrest

Park, Jang Su; Park, Su Jung; Peng, Xiaodong; Wang, Mu; Yu, Myeong Ae; Lee, Suk‐Hee

doi:10.1074/jbc.274.45.32520

Cited by 52 publications

(38 citation statements)

References 66 publications

(70 reference statements)

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“…Both of these proteins have been associated with increased survival after stress. RPA protein can reverse the replication arrest induced by UV radiation (27), whereas expression of thioredoxin is associated with UV resistance (28). To evaluate the general effect of A18 hnRNP on cell survival after genotoxic stress, we first established a cell line expressing reduced levels of A18 hnRNP by stably transfecting an antisense vector for A18 hnRNP in RKO cells.…”

Section: A18 Hnrnp Translocates To the Cytoplasm After Exposure Tomentioning

confidence: 99%

The UV-inducible RNA-binding Protein A18 (A18 hnRNP) Plays a Protective Role in the Genotoxic Stress Response

Yang

2001

Journal of Biological Chemistry

127

137

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We have previously shown that specific RNA-binding proteins (RBP) are activated by genotoxic stress. The role and function of these stress-activated RBP are, however, poorly understood. The data presented here indicate that the RBP A18 heterogeneous ribonucleoprotein (hnRNP) is induced and translocated from the nuclei to the cytoplasm after exposure to UV radiation. Using a new in vitro system we identified potential cellular targets for A18 hnRNP. Forty-six mRNA transcripts were identified, most of which are stress-or UVresponsive genes. Two important stress-responsive transcripts, the replication protein A (RPA2) and thioredoxin, were studied in more detail. Northwestern analyses indicate that A18 hnRNP binds specifically to the 3-untranslated region of RPA2 transcript independently of its poly(A) tail, whereas the poly(A) tail of thioredoxin mRNA reinforces binding. Overexpression of A18 hnRNP increases the mRNAs stability and consequently enhances translation in a dose-dependent manner. Moreover, cell lines expressing reduced levels of A18 hnRNP are more sensitive to UV radiation. These data suggest that A18 hnRNP plays a protective role against genotoxic stresses by translocating to the cytosol and stabilizing specific transcripts involved in cell survival.The cellular response to genotoxic and non-genotoxic stresses is complex. It includes multiple regulatory mechanisms that are generally thought to have protective roles. Cells respond to stress in a limited number of ways by adjusting regulatory components of basic processes such as replication, transcription, and/or translation. Much emphasis has been put on stress responses involving replication or the activation of specific genes in response to DNA damage (1); however, the regulation of post-transcriptional and translational events in response to stress has not been studied extensively. Post-transcriptional regulation can be mediated through interaction of regulatory proteins with an mRNA 3Ј end (2). This mechanism, which occurs in several organisms, is not fully understood. Most regulations of this type have been observed during early development of different organisms from Caenorhabditis elegans to mammals (3). One possible mechanism by which regulation of translation initiation can be mediated through the 3Ј end of an mRNA transcript has suggested that specific proteins bound to this region could contact the basal translation apparatus and influence translational activation or repression (2). A recent review (4) described the possibility for RNA-binding proteins to shuttle between cellular compartments either constitutively or in response to stress and regulate the localization, translation, or turnover of mRNAs. Post-transcriptional regulation can also occur through mRNAs stabilization. Recent studies describe the stabilization of mRNAs by specific RBPs 1 in response to hypoxia (5) or extracellular signals (6).In a previous study (7) we have shown that RNA binding activity of specific proteins can be induced by DNA-damaging agents. Induction of an ...

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Section: A18 Hnrnp Translocates To the Cytoplasm After Exposure Tomentioning

confidence: 99%

The UV-inducible RNA-binding Protein A18 (A18 hnRNP) Plays a Protective Role in the Genotoxic Stress Response

Yang

2001

Journal of Biological Chemistry

127

137

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“…78 RPA has roles in DNA replication and repair. [79][80][81] It inhibits the early strand invasion steps of HR and is inhibited by NHEJ components. 81 The only known in vitro targets of DNA PK, are DNA-PK itself, p53, and RPA.…”

Section: Introductionmentioning

confidence: 99%

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

Durant¹,

Nickoloff²

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2027 KEY WORDSBRCA1, NHEJ, HR, MRE11, RAD50, NBS1, exonuclease, cell cycle, DSB repair ABBREVIATIONS NHEJ non-homologous end-joining HR homologous recombination DSB double-strand break ACKNOWLEDGEMENTSOur research on the NHEJ/HR interface is supported by grant CA100862 from the National Cancer Institute, NIH. ReviewGood Timing in the Cell Cycle for Precise DNA Repair by BRCA1 ABSTRACTIt is now clear that large DNA-binding proteins have evolved in mammals to orchestrate the relatively ancient process of DNA recombinational repair. These proteins are recruited to accurately repair DNA double strand breaks (DSBs)-the frequent, potentially lethal and mutagenic lesions in the genomes of all organisms. An essential mammalian regulator of DSB repair is BRCA1. Heterozygous BRCA1 mutations predispose individuals to breast, ovarian and other secondary cancers. BRCA1-defective cells exhibit reduced DSB repair, sensitivity to a wide range of DNA damaging agents, genomic instability and defects in the S-phase checkpoint, transcription and chromatin remodelling. DSBs can be repaired by RAD51/RPA-dependent homologous recombination (HR) or DNA-PK-dependent nonhomologous end-joining (NHEJ). Both of these pathways can be imprecise and mutagenic. BRCA1 plays a central role in promoting accurate repair by both HR and NHEJ. Consistent with recent evidence, we have assembled a novel cell-cycle-dependent model in which DNA-PK inhibits RPA in S-phase of the cell cycle, while BRCA1 inhibits the exonuclease processivity of the MRE11/RAD50/NBS1 (MRN) complex and facilitates the removal of RPA in S and G 2 phase. This model provides an explanation for how BRCA1 promotes accurate DSB repair during various phases of the cell cycle and also accounts for the dual effects that BRCA1 and MRN activity have upon DNA repair and S-phase arrest.

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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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confidence: 99%

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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Involvement of DNA-dependent Protein Kinase in UV-induced Replication Arrest

Cited by 52 publications

References 66 publications

The UV-inducible RNA-binding Protein A18 (A18 hnRNP) Plays a Protective Role in the Genotoxic Stress Response

The UV-inducible RNA-binding Protein A18 (A18 hnRNP) Plays a Protective Role in the Genotoxic Stress Response

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

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

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