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Ubiquitin chromatin remodelling after DNA damage is associated with the expression of key cancer genes and pathways

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Abstract

Modification of the cancer-associated chromatin landscape in response to therapeutic DNA damage influences gene expression and contributes to cell fate. The central histone mark H2Bub1 results from addition of a single ubiquitin on lysine 120 of histone H2B and is an important regulator of gene expression. Following treatment with a platinum-based chemotherapeutic, there is a reduction in global levels of H2Bub1 accompanied by an increase in levels of the tumor suppressor p53. Although total H2Bub1 decreases following DNA damage, H2Bub1 is enriched downstream of transcription start sites of specific genes. Gene-specific H2Bub1 enrichment was observed at a defined group of genes that clustered into cancer-related pathways and correlated with increased gene expression. H2Bub1-enriched genes encompassed fifteen p53 target genes including PPM1D, BTG2, PLK2, MDM2, CDKN1A and BBC3, genes related to ERK/MAPK signalling, those participating in nucleotide excision repair including XPC, and genes involved in the immune response and platinum drug resistance including POLH. Enrichment of H2Bub1 at key cancer-related genes may function to regulate gene expression and influence the cellular response to therapeutic DNA damage.

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Acknowledgements

Dr Michael Hahn is acknowledged for the initial cloning of wt p53.

Funding

This project was supported by a Research Scholar Award from the Sydney Vital Translational Cancer Research Centre, Cancer Institute NSW [to A.J.C.] and project Grant from the Cancer Council NSW [RG13-10; to D.J.M.]. A.J.C. was supported by an Australian Postgraduate Award and Northern Clinical School Top-Up Scholarship. D.J.M. was supported by the Australian Research Council (ARC) (ARC Future Fellowship [FT100100489]) and National Health and Medical Research Council (NHMRC) (NHMRC Senior Research Fellowship [APP1004799]).

Author information

Author notes

  1. Alexander J. Cole

    Present address: Department of Medicine, Magee Women’s Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

  2. Kristie-Ann Dickson & Deborah J. Marsh

    Present address: Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia

  3. Jaynish S. Shah

    Present address: Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia

Authors and Affiliations

  1. Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia

    Alexander J. Cole, Kristie-Ann Dickson, Jaynish S. Shah, Roderick Clifton-Bligh & Deborah J. Marsh

  2. Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    Christopher Liddle

  3. Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, UNSW, Sydney, NSW, Australia

    Clare Stirzaker

  4. St. Vincent’s Clinical School, UNSW Medicine, UNSW, Sydney, NSW, Australia

    Clare Stirzaker

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Supplementary file1 (DOC 68 kb)

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Suppl. Fig. 1 Cisplatin dose curves and maximal inhibitory concentrations (IC50, IC75, IC80) in µM for A2780, HEY1, MCF7, SKOV3, H1299, Kuramochi and OVCAR-3 (N = 3-4) (JPG 2248 kb)

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Suppl. Fig. 2 University of California Santa Cruz (UCSC) genome browser hg19 images of representative H2Bub1-enriched genes in response to cisplatin. a, POLH1, b, EGR1 and c, TOB1. RNA-seq and ChIP-seq signals are shown, as is the layered image of the active transcription mark H3K27Ac of seven cell lines from ENCODE. Exonic regions are marked by boxes in RefSeq tracks. (JPG 3755 kb)

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Suppl. Fig. 3 STRING analysis of 132 H2Bub1 enriched genes in A2780 cells following treatment with an IC75 dose of cisplatin for 24 h. Strings represent known interactions from either curated databases (aqua) or that have been experimentally determined (magenta); predicted interactions (red, green or blue), or other interactions from text mining (lime), co-expression (black) or protein homology (purple) (JPG 2921 kb)

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Suppl. Fig. 4 Increased H2Bub1 enrichment in the coding region of p53 target genes in response to cisplatin [IC75 or IC80 dose levels] is observed in wild-type p53 cells (MCF7) compared to mutant p53 cells (Kuramochi). a, MCF7 wt p53 cells treated with saline (sal.) or cisplatin (cisp.; IC75 dose, Suppl. Fig. 1) for 24 h underwent ChIP with anti-H2Bub1 or IgG antibodies followed by qRT-PCR using either primers within (+) or downstream (-) of the coding regions of p53 target genes. Data within replicates was normalized to the experimental mean and presented as mean ± SEM (N = 5) analyzed using one-way ANOVA with Tukey’s post-hoc test. Right hand panel shows expression of p53 target genes in MCF7 cells in response to an IC75 dose of cisplatin (c), or saline (s) for 24 h (N = 4; data expressed relative to saline treated cells (one-sample t test); GOI, gene of interest). b, Kuramochi mutant p53 cells treated with saline or an IC80 dose of cisplatin (Suppl. Fig. 1) for 24 h underwent ChIP and qRT-PCR as above (N = 3). Right hand panel shows expression of p53 target genes in Kuramochi cells in response to an IC80 dose of cisplatin as above (N = 4). (* P < 0.05, ** P < 0.005) (JPG 1115 kb)

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Suppl. Fig. 5 Inhibition of transcriptional elongation after DNA damage inhibits H2Bub1 enrichment at p53 target genes. a, Expression levels of MDM2 were assessed relative to the reference gene HMBS in A2780 cells treated with saline or IC75 doses of cisplatin (9.9 µM) for 16 h, followed by treatment with DMSO (vehicle) or 50 µM DRB for 5 h. Data within replicates (N=3) was normalized to the saline DMSO treatment and presented as mean ± SEM analyzed using one-way ANOVA with Tukey’s post-hoc test. Specific reduction in MDM2 levels was observed in cells treated with cisplatin and DRB compared to cells treated with cisplatin and DMSO (vehicle) (** P < 0.001). b, ChIP-qPCR data showing that H2Bub1 enrichment is significantly decreased in A2780 cells following DNA damage with cisplatin and treatment with the transcriptional inhibitor DRB in p53 target genes (+, primers within the coding region; -, primers downstream of the coding region). Data within replicates was normalized to the experimental mean and presented as mean ± SEM (N = 3) analyzed using one-way ANOVA with Tukey’s post-hoc test (** P < 0.001) (JPG 705 kb)

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Cole, A.J., Dickson, KA., Liddle, C. et al. Ubiquitin chromatin remodelling after DNA damage is associated with the expression of key cancer genes and pathways. Cell. Mol. Life Sci. 78, 1011–1027 (2021). https://doi.org/10.1007/s00018-020-03552-5

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