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

Affiliation

Cole AJ(1)(2), Dickson KA(1)(3), Liddle C(4), Stirzaker C(5)(6), Shah JS(1)(7), Clifton-Bligh R(1), Marsh DJ(8)(9).
Author information:
(1)Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
(2)Department of Medicine, Magee Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
(3)Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
(4)Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
(5)Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, UNSW, Sydney, NSW, Australia.
(6)St. Vincent's Clinical School, UNSW Medicine, UNSW, Sydney, NSW, Australia.
(7)Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
(8)Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia. [Email]
(9)Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia. [Email]

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.