Gene Structure and Function

Theme Co-Leads

Professor Jo Morris

Professor Jo Morris

Professor of Molecular Genetics

 

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Professor Ferenc Mueller

Professor Ferenc Mueller

Professor in Developmental Genetics

 

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The DNA within the nuclei of our cells carries the information to generate the machinery of the cell, the cell itself, our tissues and then the whole human. While each DNA blueprint, or gene, encodes for a different machine or structure, the genome, the collection of DNA wrapped up inside the nucleus, is much more active than a quiet library of neatly stacked blue-prints.

The way the DNA is structured, wrapped and read is fundamental to how and when the blueprint genes are read. Promoters, enhancers and physical interactions between regions of DNA are important in ways that are only now becoming apparent, directing phases of development, and often perturbed in cancers. The proper copying and repair of DNA to maintain the correct sequence and structure of genomes is critical to the proper function of cells, and repair and replication is frequently disrupted in cancers and targeted by cancer treatments. Within the genome, many processes occur almost simultaneously so that the regulation of possibly chaotic access is tightly controlled. The Genome Stucture Function section of the Institute of Cancer and Genomic Sciences  investigates the fundamentals of the active information database that is our genome, in normal and disease states. We aim to use our understanding of these processes to improve human health and prevent, and treat human disease.

Replication forkDNA Replication, Stability and Repair

Our research is defining the normal mechanisms of DNA replication and repair, with the aim of understanding how it is deregulated in cancer cells. We are investigating the impact of specific classes of gene mutations, such as ATM, BRCA1, and MYBL2 on genome integrity. We examine the impact that processes such as transcription and replication have on genome stability. 

We recently discovered new ways the BRCA1 gene functions which could help expand our understanding of the development of ovarian and breast cancers. Results showed BRCA1 changes shape in order to protect vulnerable DNA until the copying machinery can be restarted. In addition, in some patients with a personal or family history of breast and ovarian cancer, the protective role of BRCA1 in DNA-copying is disabled - while its break repair function is still active.

Gene regulation diagram

Gene Structure and Regulation

Our basic research covers cancer cell and stem cell biology, viral oncology (EBV and HPV) and genome biology. We use high throughput methods to determine how genetic abnormalities unravel the complex regulatory networks that underlie cancer. In parallel we are studying the molecular pathways that control the normal development and differentiation of stem cells.

Current research includes a £1.3 million grant from the MRC to test combinations of drugs that target the signalling molecule FLT3 together with the transcription factor RUNX1 in Acute Myeloid Leukaemia.

 

Spotlight on DNA Replication

Nature  571: 521-527 (2019). Daza-Martin M, Starowicz K, Jamshad M, Tye S, Ronson GE, MacKay HL, Chauhan AS, Walker AK, Stone HR, Beesley JFJ, Coles JL, Garvin AJ, Stewart GS, McCorvie TJ, Zhang X, Densham RM, JR Morris. Isomerization of BRCA1-BARD1 promotes replication fork protection.  

Diagram of BRCA as described below

BRCA1 is a gene required for genome stability and is a frequent target of mutations in breast cancer. Here the group of Jo Morris shows that the functional activation of the BRCA1 protein involves a conformational change in its structure.

BRCA1 phosphorylation by CDK1/2 followed by isomerization by PIN1 enhances the ability of BARD1 to associate with RAD51 (brown) and thereby promotes replication fork protection.

Selected Highlights from DNA Replication, Stability and Repair

J Clinical Investigation 130:4069-4080 (2020). Zarrizi R, MR Higgs, K Vossgrone, M Rossing, B Bertelsen, M Bose, . . . GS Stewart, FC Nielsen, CS Sorensen. Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability.

J Gen Virol 101:873-883 (2020). Hollingworth R, GS Stewart and RJ Grand. Productive herpesvirus lytic replication in primary effusion lymphoma cells requires S-phase entry.

Mol Psychiatry  (2020). Kummeling J, DE Stremmelaar, N Raun, MRF Reijnders, MH Willemsen, M Ruiterkamp-Versteeg, . . . MR Higgs, JM Kramer, T Kleefstra. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Nat Commun 11:4287 (2020). van Schie JJM, A Faramarz, JA Balk, GS Stewart, E Cantelli, AB Oostra, . . . J de Lange. Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.

J Clin Invest 130:4069-4080 (2020). Zarrizi R, MR Higgs, K Vossgrone, M Rossing, B Bertelsen, M Bose, . . . CS Sorensen. Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability.

Nat Commun 11:3951 (2020). Zhang J, MA Bellani, RC James, D Pokharel, Y Zhang, JJ Reynolds, . . . SG Stewart, MM Seidman. DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain.

Nature 571:521-527 (2019). Daza-Martin M, K Starowicz, M Jamshad, S Tye, GE Ronson, HL MacKay, . . . JR Morris. Isomerization of BRCA1-BARD1 promotes replication fork protection.

Genes Dev 33:333-347 (2019). Garvin AJ, AK Walker, RM Densham, AS Chauhan, HR Stone, HL Mackay, . . . JR Morris. The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms.

Cancer Res 78:5767-5779 (2018). Bayley R, D Blakemore, L Cancian, S Dumon, G Volpe, C Ward, . . . MR Higgs, GS Stewart, E Petermann, P Garcia. MYBL2 supports DNA double strand break repair in haematopoietic stem cells.

Cell Rep 25:2061-2069 e2064 (2018). Bowry A, AL Piberger, P Rojas, M Saponaro and E Petermann. BET Inhibition Induces HEXIM1- and RAD51-Dependent Conflicts between Transcription and Replication.

Mol Cell 71:25-41 e26 (2018). Higgs MR, K Sato, JJ Reynolds, S Begum, R Bayley, A Goula, . . . GS Stewart. Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.

Nat Commun 9:746 (2018). Ronson GE, AL Piberger, MR Higgs, AL Olsen, GS Stewart, PJ McHugh, . . . E Petermann, ND Lakin. PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation.

Nat Commun 9:229 (2018). Uckelmann M, RM Densham, R Baas, HHK Winterwerp, A Fish, TK Sixma and JR Morris. USP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A.

Nature 559:285-289 (2018). Zimmermann M, O Murina, MAM Reijns, A Agathanggelou, R Challis, Z Tarnauskaite, . . . T Stankovic, AP Jackson, D Durocher. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.

Mol Cell 65:900-916 e907 (2017). Clarke TL, MP Sanchez-Bailon, K Chiang, JJ Reynolds, J Herrero-Ruiz, TM Bandeiras, . . . CC Davies. PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.

J Virol 91 (2017). Campos-Leon K, K Wijendra, A Siddiqa, I Pentland, KM Feeney, A Knapman, . . . JL Parish. Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication.

Cell Rep 21:3498-3513 (2017). Chiang K, AE Zielinska, AM Shaaban, MP Sanchez-Bailon, J Jarrold, TL Clarke, . . . CC Davies. PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression.

Nat Genet 49:537-549 (2017). Reynolds JJ, LS Bicknell, P Carroll, MR Higgs, R Shaheen, JE Murray, . . . GS Stewart. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

Nat Cell Biol 19:468-479 (2017). Sonneville R, SP Moreno, A Knebel, C Johnson, CJ Hastie, A Gartner, . . . K Labib. CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.

Cell 168:843-855 e813 (2017). Williamson L, M Saponaro, S Boeing, P East, R Mitter, T Kantidakis, . . . JQ Svejstrup. UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene.

Nat Commun 7:13087 (2016). Kotsantis P, LM Silva, S Irmscher, RM Jones, L Folkes, N Gromak and E Petermann. Increased global transcription activity as a mechanism of replication stress in cancer.

PLoS Genet 12:e1005945 (2016). Byrd PJ, GS Stewart, A Smith, C Eaton, AJ Taylor, C Guy, . . . AM Taylor. A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.

Nat Struct Mol Biol 23:647-655 (2016). Densham RM, AJ Garvin, HR Stone, J Strachan, RA Baldock, M Daza-Martin, . . . JR Morris. Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection.

Nat Genet 48:36-43 (2016). Harley ME, O Murina, A Leitch, MR Higgs, LS Bicknell, G Yigit, . . . AP Jackson. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

Genes Dev 30:408-420 (2016). Kantidakis T, M Saponaro, R Mitter, S Horswell, A Kranz, S Boeing, . . . JQ Svejstrup. Mutation of cancer driver MLL2 results in transcription stress and genome instability.

Blood 127:582-595 (2016). Kwok M, N Davies, A Agathanggelou, E Smith, C Oldreive, E Petermann, . . . T Stankovic. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

Dev Cell 38:358-370 (2016). Monteiro R, P Pinheiro, N Joseph, T Peterkin, J Koth, E Repapi, . . . R Patient. Transforming Growth Factor beta Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells.

Mol Cell 59:462-477 (2015). Higgs MR, JJ Reynolds, A Winczura, AN Blackford, V Borel, ES Miller, . . . GS Stewart. BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks.

Science 346:477-481 (2014). Moreno SP, R Bailey, N Campion, S Herron and A Gambus. Polyubiquitylation drives replisome disassembly at the termination of DNA replication.

Cell 157:1037-1049 (2014). Saponaro M, T Kantidakis, R Mitter, GP Kelly, M Heron, H Williams, . . . JQ Svejstrup. RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress.

EMBO J 32:1556-1567 (2013). Davies CC, A Chakraborty, ME Diefenbacher, M Skehel and A Behrens. Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation.

EMBO Rep 14:975-983 (2013). Garvin AJ, RM Densham, SA Blair-Reid, KM Pratt, HR Stone, D Weekes, . . . JR Morris. The deSUMOylase SENP7 promotes chromatin relaxation for homologous recombination DNA repair. 

Spotlight on Cancer Genomics

Nature Genetics 51:151-162 (2019). Assi SA, MR Imperato, DJL Coleman, A Pickin, S Potluri, A Ptasinska, . . . PN CockerillC Bonifer. Subtype-specific regulatory network rewiring in acute myeloid leukemia. 

Gene structure and regulation diagram as detailed below

A study by Constanze Bonifer and Peter Cockerill has revealed the roles that different types of gene mutations play in causing acute myeloid leukaemia. Epigenetic profiling of regulatory elements revealed that mutation-specific subsets of AML have distinct patterns of gene expression. Each subset was controlled by distinct gene regulatory networks linked to mutations in transcription factors and signalling molecules This research brings us one step closer to being able to provide tailored and targeted treatment specific to individual patients, increasing their chances of survival.

Selected Highlights from Gene Structure and Regulation

Life Science Alliance 4 (2021). Kellaway SG, P Keane, B Edginton-White, K Regha, E Kennett and C Bonifer. Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories.

Cell Reports 34:108759 (2021). Wang J, P Rojas, J Mao, M Muste Sadurni, O Garnier, S Xiao, . . . MR Higgs, P Garcia,  M Saponaro. Persistence of RNA transcription during DNA replication delays duplication of transcription start sites until G2/M.

Frontiers in Immunology 12:642807 (2021). Bevington SL, R Fiancette, DW Gajdasik, P Keane, JK Soley, CM Willis, . . . PN Cockerill. Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo.

EMBO Reports 22:e51120 (2021). Blakemore D, N Vilaplana-Lopera, R Almaghrabi, E Gonzalez, M Moya, C Ward, . .A Gambus, E Petermann, GS Stewart, P Garcia. MYBL2 and ATM suppress replication stress in pluripotent stem cells.

Scientific Reports 11:3009 (2021). Halsall JA, S Andrews, F Krueger, CE Rutledge, G Ficz, W Reik and BM Turner. Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle.

Cell Reports 35:109010 (2021). Potluri S, SA Assi, PS Chin, DJL Coleman, A Pickin, S Moriya, . . . PN Cockerill, C Bonifer. Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1.

J General Virology 101:873-883 (2020). Hollingworth R, GS Stewart and RJ Grand. Productive herpesvirus lytic replication in primary effusion lymphoma cells requires S-phase entry.

EMBO J:e105220 (2020). Bevington SL, P Keane, JK Soley, S Tauch, DW Gajdasik, R Fiancette, . . . PN Cockerill. IL-2/IL-7-inducible factors pioneer the path to T cell differentiation in advance of lineage-defining factors. doi: 10.15252/embj.2020105220

Cell Rep 31:107748 (2020). Bevington SL, STH Ng, GJ Britton, P Keane, DC Wraith and PN Cockerill. Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes.

Commun Biol 3:71 (2020). Dobrzycki T, CB Mahony, M Krecsmarik, C Koyunlar, R Rispoli, J Peulen-Zink, . . . R Monteiro. Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis.

Haematologica  (2020). Kellaway SG, P Keane, E Kennett and C Bonifer. RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks. DOI: 10.3324/haematol.2019.241885

Life Sci Alliance 3 (2020). Kwon SY, K Massey, MA Watson, T Hussain, G Volpe, CD Buckley, . . . P Badenhorst. Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO.

Cell Rep 31:107691 (2020). Nafria M, P Keane, ES Ng, EG Stanley, AG Elefanty and C Bonifer. Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells.

Nucleic Acids Res 48:8374-8392 (2020). Wragg JW, L Roos, D Vucenovic, N Cvetesic, B Lenhard and F Muller. Embryonic tissue differentiation is characterized by transitions in cell cycle dynamic-associated core promoter regulation.

J Virol  (2020). Molloy DP and RJ Grand. Structural determinants within the adenovirus early region 1A protein spacer region necessary for tumourigenesis.

Nat Genet 51:151-162 (2019). Assi SA, MR Imperato, DJL Coleman, A Pickin, S Potluri, A Ptasinska, . . . PN Cockerill, C Bonifer. Subtype-specific regulatory network rewiring in acute myeloid leukemia.

Nat Commun 10:3577 (2019). Bonkhofer F, R Rispoli, P Pinheiro, M Krecsmarik, J Schneider-Swales, IHC Tsang, . . . R Monteiro, T Peterkin, R Patient. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium.

Nat Commun 10:691 (2019). Hadzhiev Y, HK Qureshi, L Wheatley, L Cooper, A Jasiulewicz, H Van Nguyen, . . . F Muller. A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation.

Cell Rep 28:3022-3031 e3027 (2019). Ptasinska A, A Pickin, SA Assi, PS Chin, L Ames, R Avellino, . . . C Bonifer. RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPalpha- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction.

Cancer Cell 34:674-689 e678 (2018). de Boer B, J Prick, MG Pruis, P Keane, MR Imperato, J Jaques, . . . C Bonifer, JJ Schuringa. Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones.

Cancer Cell 34:626-642 e628 (2018). Martinez-Soria N, L McKenzie, J Draper, A Ptasinska, H Issa, S Potluri, . . . C Bonifer, O Heidenreich. The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

Cell Rep 24:1496-1511 e1498 (2018). Ward C, G Volpe, P Cauchy, A Ptasinska, R Almaghrabi, D Blakemore, . . . P Garcia. Fine-Tuning Mybl2 Is Required for Proper Mesenchymal-to-Epithelial Transition during Somatic Reprogramming.

J Immunol 199:2652-2667 (2017). Brignall R, P Cauchy, SL Bevington, B Gorman, AO Pisco, J Bagnall, . . . P Cockerill, P Paszek. Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

J Virol 91 (2017). Harris L, L McFarlane-Majeed, K Campos-Leon, S Roberts and JL Parish. The Cellular DNA Helicase ChlR1 Regulates Chromatin and Nuclear Matrix Attachment of the Human Papillomavirus 16 E2 Protein and High-Copy-Number Viral Genome Establishment.

Cell Rep 19:1654-1668 (2017). Loke J, SA Assi, MR Imperato, A Ptasinska, P Cauchy, Y Grabovska, . . . C Bonifer. RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML.

Nucleic Acids Res 45:9874-9888 (2017). Stanulovic VS, P Cauchy, SA Assi and M Hoogenkamp. LMO2 is required for TAL1 DNA binding activity and initiation of definitive haematopoiesis at the haemangioblast stage.

Sci Rep 7:11148 (2017). Volpe G, DS Walton, DE Grainger, C Ward, P Cauchy, D Blakemore, . . . J Frampton. Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature.

EMBO J 35:515-535 (2016). Bevington SL, P Cauchy, J Piper, E Bertrand, N Lalli, RC Jarvis, . . . PN Cockerill. Inducible chromatin priming is associated with the establishment of immunological memory in T cells.

PLoS Genet 12:e1005969 (2016). Kwon SY, V Grisan, B Jang, J Herbert and P Badenhorst. Genome-Wide Mapping Targets of the Metazoan Chromatin Remodeling Factor NURF Reveals Nucleosome Remodeling at Enhancers, Core Promoters and Gene Insulators.

Epigenetics Chromatin 9:52 (2016). Wiersma M, M Bussiere, JA Halsall, N Turan, R Slany, BM Turner and BM Turner, KP Nightingale. Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes.

Leukemia  (2016). Clarke M, G Volpe, L Sheriff, D Walton, C Ward, W Wei, . . . J Frampton. Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.

Dev Cell 36:572-587 (2016). Goode DK, N Obier, MS Vijayabaskar, ALM Lie, AJ Lilly, R Hannah, . . . C Bonifer. Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation.

Dev Cell 38:358-370 (2016). Monteiro R, P Pinheiro, N Joseph, T Peterkin, J Koth, E Repapi, . . . R Patient. Transforming Growth Factor beta Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells.

Cell Rep 12:821-836 (2015). Cauchy P, SR James, J Zacarias-Cabeza, A Ptasinska, MR Imperato, SA Assi, . . . PN Cockerill. Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature.

J Virol 89:4770-4785 (2015). Paris C, I Pentland, I Groves, DC Roberts, SJ Powis, N Coleman, . . . JL Parish. CCCTC-Binding Factor Recruitment to the Early Region of the Human Papillomavirus 18 Genome Regulates Viral Oncogene Expression.

Nat Commun 6:7203 (2015). Regha K, SA Assi, O Tsoulaki, J Gilmour, G Lacaud and C Bonifer. Developmental-stage-dependent transcriptional response to leukaemic oncogene expression.

Nature 507:381-385 (2014). Haberle V, N Li, Y Hadzhiev, C Plessy, C Previti, C Nepal, . . . F Muller, B Lenhard. Two independent transcription initiation codes overlap on vertebrate core promoters.

Cell reports 8:1974-1988 (2014). Ptasinska A, SA Assi, N Martinez-Soria, MR Imperato, J Piper, P Cauchy, . . . C Bonifer. Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal.

Development 141:715-724 (2014). Roberts JA, I Miguel-Escalada, KJ Slovik, KT Walsh, Y Hadzhiev, R Sanges, . . . F Muller. Targeted transgene integration overcomes variability of position effects in zebrafish.

Leukemia 27:661-670 (2013). Clarke M, S Dumon, C Ward, R Jager, S Freeman, B Dawood, . . . J Frampton, P Garcia. MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia.

Genome Res 23:1938-1950 (2013). Nepal C, Y Hadzhiev, C Previti, V Haberle, N Li, H Takahashi, . . . F Muller. Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis.

Leukemia 27:1487-1496 (2013). Volpe G, DS Walton, W Del Pozzo, P Garcia, E Dasse, LP O'Neill, . . . J Frampton, S Dumon. C/EBPalpha and MYB regulate FLT3 expression in AML