DNA Replication, Stability and Repair

 

Replication fork 1250 x 400 for ICGS DNA replication page

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.

 Theme Lead

jo morrisProfessor Jo Morris

Professor of Molecular Genetics

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Research groups

DNA Replication, Stability and Repair
ResearcherResearch Group
Aga Gambus Regulation of DNA replication by SUMO and ubiquitin
Paloma Garcia Genome stability in stem cells
Martin Higgs Lysine methylation and DNA damage
Jo Morris Breast cancer mutations that suppress DNA repair
Eva Petermann Petermann DNA replication and repair
Marco Saponaro        Transcription-mediated genome instability
Stephen Smerdon Genome stability and DNA repair
Tatjana Stankovic Genetics and biology of B cell malignancies
Grant Stewart Role of DNA damage response genes in disease
Malcolm Taylor Role of ATM in DNA repair and cancer
Joanna Parish HPV gene expression and replication
Andrew Turnell Adenovirus biology and cellular transformation
Bryan Turner Regulation of histone modifications

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.  

BRCA image for DNA replication pubs page

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 this Research Theme

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.