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{"title"=>"Etoposide induces nuclear re-localisation of AID", "type"=>"journal", "authors"=>[{"first_name"=>"Laurens J.", "last_name"=>"Lambert", "scopus_author_id"=>"55992016900"}, {"first_name"=>"Simon", "last_name"=>"Walker", "scopus_author_id"=>"57198868819"}, {"first_name"=>"Jack", "last_name"=>"Feltham", "scopus_author_id"=>"57200333785"}, {"first_name"=>"Heather J.", "last_name"=>"Lee", "scopus_author_id"=>"16316055200"}, {"first_name"=>"Wolf", "last_name"=>"Reik", "scopus_author_id"=>"7007161076"}, {"first_name"=>"Jonathan", "last_name"=>"Houseley", "scopus_author_id"=>"8632992500"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84891757651", "pmid"=>"24324754", "sgr"=>"84891757651", "doi"=>"10.1371/journal.pone.0082110", "isbn"=>"1932-6203", "issn"=>"19326203", "pui"=>"372069597"}, "id"=>"9025a02e-2625-3733-94d1-d83282a676c9", "abstract"=>"During B cell activation, the DNA lesions that initiate somatic hypermutation and class switch recombination are introduced by activation-induced cytidine deaminase (AID). AID is a highly mutagenic protein that is maintained in the cytoplasm at steady state, however AID is shuttled across the nuclear membrane and the protein transiently present in the nucleus appears sufficient for targeted alteration of immunoglobulin loci. AID has been implicated in epigenetic reprogramming in primordial germ cells and cell fusions and in induced pluripotent stem cells (iPS cells), however AID expression in non-B cells is very low. We hypothesised that epigenetic reprogramming would require a pathway that instigates prolonged nuclear residence of AID. Here we show that AID is completely re-localised to the nucleus during drug withdrawal following etoposide treatment, in the period in which double strand breaks (DSBs) are repaired. Re-localisation occurs 2-6 hours after etoposide treatment, and AID remains in the nucleus for 10 or more hours, during which time cells remain live and motile. Re-localisation is cell-cycle dependent and is only observed in G2. Analysis of DSB dynamics shows that AID is re-localised in response to etoposide treatment, however re-localisation occurs substantially after DSB formation and the levels of re-localisation do not correlate with γH2AX levels. We conclude that DSB formation initiates a slow-acting pathway which allows stable long-term nuclear localisation of AID, and that such a pathway may enable AID-induced DNA demethylation during epigenetic reprogramming.", "link"=>"http://www.mendeley.com/research/etoposide-induces-nuclear-relocalisation-aid", "reader_count"=>20, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>9, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>9, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>0}

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• http://doi.org/10.1371/journal.pgen.1007968
• http://doi.org/10.18632/oncotarget.7603
• http://doi.org/10.1371/journal.pgen.1005411

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• {"files"=>["https://ndownloader.figshare.com/files/1303481"], "description"=>"<p>A) AID localisation in NIH/3T3 cells transiently transfected with FLAG-AID and treated for 2 hours with 200µM etoposide or vehicle control (DMSO). Most etoposide-treated cells were indistinguishable from controls, however, the rare cells shown with nuclear AID (<1% transfected cells) in the drug treated sample were never observed in the controls. B) AID distribution after 24 and 72 minutes treatment with 200µM etoposide compared to γH2AX formation. Images were captured at equivalent exposure times to allow visual comparison of signal intensity. C) Percentage of transfected cells showing nuclear AID localisation after 2 hours treatment with 200µM etoposide followed by drug withdrawal for 0, 2, 4, 6 and 24 hours. Data is from three independent experiments, two using FLAG-AID and one using GFP-AID constructs to ensure that the specific tag was not the source of the effect. Error bars represent ±1 s.e., *** p<0.01, * p<0.05 for Student’s <i>t</i>-test comparing given time point to pre-treatment (time=0). D) AID localisation after 2 hours etoposide treatment followed by 4 and 6 hours drug withdrawal. Scale bars at bottom right of each image indicate 10µm.</p>", "links"=>[], "tags"=>[], "article_id"=>868535, "categories"=>["Biological Sciences"], "users"=>["Laurens J. Lambert", "Simon Walker", "Jack Feltham", "Heather J. Lee", "Wolf Reik", "Jonathan Houseley"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0082110.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Etoposide_induces_AID_re_localisation_/868535", "title"=>"Etoposide induces AID re-localisation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-04 04:12:20"}
• {"files"=>["https://ndownloader.figshare.com/files/1303485"], "description"=>"<p>A) Montage of frames from live-cell imaging of an NIH/3T3 cell expressing GFP-AID, treated for 2 hours with 200µM etoposide and then monitored after drug withdrawal. Each frame represents 40 minutes. This video can be seen in full in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082110#pone.0082110.s004\" target=\"_blank\">Movie S1</a>. B) Montage of two cells undergoing cytoplasmic to nuclear re-localisation of AID after etoposide withdrawal. Frames are shown at 10 minute intervals, t=0 at the addition of etoposide, first frame shown here is at etoposide removal. This video can be seen in full in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082110#pone.0082110.s006\" target=\"_blank\">Movie S3</a>.</p>", "links"=>[], "tags"=>[], "article_id"=>868538, "categories"=>["Biological Sciences"], "users"=>["Laurens J. Lambert", "Simon Walker", "Jack Feltham", "Heather J. Lee", "Wolf Reik", "Jonathan Houseley"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0082110.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_AID_re_localisation_/868538", "title"=>"Dynamics of AID re-localisation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-04 04:12:20"}
• {"files"=>["https://ndownloader.figshare.com/files/1303489"], "description"=>"<p>A) Co-staining of AID and phospho-H3 S10 in NIH/3T3 cells treated for 2 hours with 200µM etoposide, sampled 2 hours (upper panel) or 6 hours (lower panel) after drug withdrawal. White arrows indicate phospho-H3 S10 positive cells with nuclear AID, red arrows indicate a phospho-H3 S10 positive cell with cytoplasmic AID. B) Proportion of cells showing nuclear AID with and without phospho-H3 S10 across a time course of 2 hours 200µM etoposide treatment followed by drug withdrawal. C) Co-staining of AID and cyclin B1 in cells constitutively expressing FLAG-AID. Cells were treated with 200µM etoposide for 2 hours then allowed to recover for 5 hours before staining. White arrows indicate cells with nuclear AID and nuclear Cyclin B1, red arrows indicate a cell with cytoplasmic AID and nuclear cyclin B1, yellow arrows indicate a cell with cytoplasmic AID and cytoplasmic cyclin B1. D) Quantification of cells with nuclear cyclin B1, nuclear AID, or both. Error bars represent ±1 s.e., *** p<0.01, * p<0.05 for Student’s <i>t</i>-test, n=3 experiments with quantification of >100 cells each. </p>", "links"=>[], "tags"=>[], "article_id"=>868542, "categories"=>["Biological Sciences"], "users"=>["Laurens J. Lambert", "Simon Walker", "Jack Feltham", "Heather J. Lee", "Wolf Reik", "Jonathan Houseley"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0082110.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_cycle_association_of_AID_re_localisation_/868542", "title"=>"Cell cycle association of AID re-localisation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-04 04:12:20"}
• {"files"=>["https://ndownloader.figshare.com/files/1303497"], "description"=>"<p>A) Western blot showing γH2AX levels in NIH/3T3 cells treated for 2 hours with 200µM etoposide or 200µg/ml bleomycin, the concentration used in [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082110#B47\" target=\"_blank\">47</a>]. Histone H3 and α-tubulin are shown as loading controls, quantification of γH2AX is relative to tubulin. B) Western blot of γH2AX levels in NIH/3T3 cells after 2 hours treatment with given concentrations of etoposide and bleomycin. Controls as in A, quantification of γH2AX is relative to tubulin. C) Localisation of AID in a stable NIH/3T3 cell line expressing FLAG-AID, treated with bleomycin and etoposide at different doses for 2 hours and then allowed to recover for 5 hours. White arrows indicate cells with nuclear AID. Scale bars at bottom right of each image indicate 10µm. D) Quantification of cells shown in C with nuclear AID under different drug treatments. E) AID nuclear localisation with increasing etoposide concentration, cells treated as in C. Error bars represent ±1 s.e., * p<0.05 for Student’s <i>t</i>-test, n=3 samples per drug treatment except n=2 for 20µM etoposide and n=5 for 200µM etoposide, >100 cells were counted in each sample.</p>", "links"=>[], "tags"=>[], "article_id"=>868546, "categories"=>["Biological Sciences"], "users"=>["Laurens J. Lambert", "Simon Walker", "Jack Feltham", "Heather J. Lee", "Wolf Reik", "Jonathan Houseley"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0082110.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DSB_requirement_for_AID_nuclear_localisation_/868546", "title"=>"DSB requirement for AID nuclear localisation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-04 04:12:20"}
• {"files"=>["https://ndownloader.figshare.com/files/1303506", "https://ndownloader.figshare.com/files/1303507", "https://ndownloader.figshare.com/files/1303508", "https://ndownloader.figshare.com/files/1303509", "https://ndownloader.figshare.com/files/1303510", "https://ndownloader.figshare.com/files/1303511", "https://ndownloader.figshare.com/files/1303512", "https://ndownloader.figshare.com/files/1303513"], "description"=>"<div><p>During B cell activation, the DNA lesions that initiate somatic hypermutation and class switch recombination are introduced by activation-induced cytidine deaminase (AID). AID is a highly mutagenic protein that is maintained in the cytoplasm at steady state, however AID is shuttled across the nuclear membrane and the protein transiently present in the nucleus appears sufficient for targeted alteration of immunoglobulin loci. AID has been implicated in epigenetic reprogramming in primordial germ cells and cell fusions and in induced pluripotent stem cells (iPS cells), however AID expression in non-B cells is very low. We hypothesised that epigenetic reprogramming would require a pathway that instigates prolonged nuclear residence of AID. Here we show that AID is completely re-localised to the nucleus during drug withdrawal following etoposide treatment, in the period in which double strand breaks (DSBs) are repaired. Re-localisation occurs 2-6 hours after etoposide treatment, and AID remains in the nucleus for 10 or more hours, during which time cells remain live and motile. Re-localisation is cell-cycle dependent and is only observed in G2. Analysis of DSB dynamics shows that AID is re-localised in response to etoposide treatment, however re-localisation occurs substantially after DSB formation and the levels of re-localisation do not correlate with γH2AX levels. We conclude that DSB formation initiates a slow-acting pathway which allows stable long-term nuclear localisation of AID, and that such a pathway may enable AID-induced DNA demethylation during epigenetic reprogramming. </p> </div>", "links"=>[], "tags"=>["re-localisation"], "article_id"=>868554, "categories"=>["Biological Sciences"], "users"=>["Laurens J. Lambert", "Simon Walker", "Jack Feltham", "Heather J. Lee", "Wolf Reik", "Jonathan Houseley"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0082110.s001", "https://dx.doi.org/10.1371/journal.pone.0082110.s002", "https://dx.doi.org/10.1371/journal.pone.0082110.s003", "https://dx.doi.org/10.1371/journal.pone.0082110.s004", "https://dx.doi.org/10.1371/journal.pone.0082110.s005", "https://dx.doi.org/10.1371/journal.pone.0082110.s006", "https://dx.doi.org/10.1371/journal.pone.0082110.s007", "https://dx.doi.org/10.1371/journal.pone.0082110.s008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Etoposide_Induces_Nuclear_Re_Localisation_of_AID_/868554", "title"=>"Etoposide Induces Nuclear Re-Localisation of AID", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-12-04 04:12:20"}

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Relative Metric

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F1000Prime