DNA Replication and Repair
Our research is defining the normal mechanisms of DNA replication and DNA repair, and how these contribute to healthy development and healthy lifespan. Understanding how the integrity of our DNA is maintained is central to preventing and treating diseases such as cancer. Inherited mutations in genes that replicate or repair DNA can underlie rare developmental conditions and contribute to earlier-onset cancers. Loss of genome integrity also plays important roles in the development and treatment of sporadic cancers, including those caused by virus infections, and in neurological disorders. Researchers within the DNA Replication and Repair Section are investigating the impact of specific genes such as BRCA1 on genome integrity, and the wider mechanisms of genome damage and integrity in development, cancer and nervous system function.
Over the last decade this theme has been highly successful at attracting major programme and project grant funding. In 2022 Jo Morris secured more than £4.9 million from the Wellcome Trust, the MRC and Horizon Europe to better understand DNA replication and repair. Eva Petermann and Jo Parish were also awarded £1.2 million by the MRC to better understand the role of oncogene activation and genomic instability in cancer initiation.
Theme Lead and Deputy Theme Lead
Jason Parsons
Professor of Radiobiology / Theme Lead
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Eva Petermann
Professor of Genome Stability / Deputy Theme Lead
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Research groups
Spotlight on the role of DONSON in kick-starting DNA replication at origins of replication
Molecular Cell Oct 10:S1097-2765(23)00761-X (2023). Cvetkovic MA, P Passaretti, A Butryn, A Reynolds-Winczura, G Kingsley, A Skagia, . . .G Stewart, A Gambus and A Costa.
A collaboration between Aga Gambus in Birmingham and Alessandro Costa in London, with contributions from Grant Stewart, Birmingham, has revealed new insights into how DNA replication helicases switch from an inactive form to an active form at DNA origins of replication. High resolution electron microscopy showed how dimers of the protein DONSON (shown here in purple in the centre) bind in between two inactive DNA replication helicases at DNA origins and load symmetrically two helicase activators: the GINS complex. This leads to a conformational change in the complexes, resulting in rotation of the MCM helicases, and the initiation of DNA replication.
Spotlight on Drugs that promote spinal cord repair after injury
Science Advances 8 (2022) eabq2611.Taylor MJ, Thompson AM, Alhajlah S, Tuxworth RI, Ahmed Z. .
Clinical and Translational Medicine 12 (2022) e962. Ahmed Z, Tuxworth RI. .
Ground-breaking recent studies from the Ahmed and Tuxworth laboratories have shown that 2 drugs designed to cure cancer can now potentially be used to promote spinal cord and optic nerve repair after injury. Anti-cancer drugs that target either ATM or CHK2 in the DNA repair pathway promote the survival of neurons and the re-growth of axons across sites of nerve damage. DNA double strand breaks in damaged neurons normally trigger a DNA damage response that blocks regrowth of axons and often results in cell death. Remarkably, inhibition of the ATM/CHK2 pathway led to a return of normal transmission of nerve impulses across damaged spinal cords or optic nerves in models of injury in animals where electrical transmission across damaged neurons had been blocked. When these drugs were given within 24 hours of spinal cord injury in animal models, they promoted full recovery of hind limb function and sensation within a few weeks. These drugs are already in development or in use for cancer and may in the future be investigated for their potential use to promote recovery from spinal cord injury in people.
Spotlight on protein modification crosstalk during DNA repair
Nature Communications 12: 6313 (2021). M-P Sanchez-Bailon M-P, S-Y Choi, ER Dufficy, K Sharma, GS McNee, E Gunnel, K Chiang, D Sahay, S Maslen, GS Stewart, JM Skehel, I Dreveny and CC Davies. Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair.
PRMT1 is an arginine methyltransferase that promotes genome stability and is upregulated in many cancers. Here, the group of Clare Davies identify the deubiquitylating enzyme USP11 as a new PRMT1 substrate, and that methylation of USP11 is required for double strand break repair. They also show that PRMT1 is a substrate for USP11, and that deubiquitylation of PRMT1 promotes PRMT1 activity towards MRE11, a component of the MRN complex, leading to efficient DNA end resection at break points. This study demonstrates the complexity of post-translational modifications that safe-guards our genome against DNA damage, but also suggests that hyper-activation could lead to chemo-resistance in cancer cells following chemo-therapy.
Spotlight on BRCA1 and 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.
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 Clin Invest 132 (2022). Abu-Libdeh B, SS Jhujh, S Dhar, JA Sommers, A Datta, GM Longo, . . . GS Stewart. .
Mol Cell 82:1924-1939 e1910 (2022). Bayley R, V Borel, RJ Moss, E Sweatman, P Ruis, A Ormrod, . . . MR Higgs. .
J Cell Sci 135 (2022). Faulkner EL, JA Pike, RM Densham, E Garlick, SG Thomas, RK Neely and JR Morris. .
J Biol Chem 298:102234 (2022). Tarcan Z, D Poovathumkadavil, A Skagia and A Gambus. .
Viruses 13 (2021). Abualfaraj T, NC Hagkarim, R Hollingworth, L Grange, S Jhujh, GS Stewart and RJ Grand.
EMBO Rep 22:e51120 (2021). Blakemore D, N Vilaplana-Lopera, R Almaghrabi, E Gonzalez, M Moya, C Ward, . . .A Gambus, E Petermann, GS Stewart, P Garcia. .
Nat Comm 12: 6313 (2021). M-P Sanchez-Bailon M-P, S-Y Choi, ER Dufficy, K Sharma, GS McNee, … CC Davies. .
Nat Commun 11:5863 (2020). Piberger AL, A Bowry, RDW Kelly, AK Walker, D Gonzalez-Acosta, LJ Bailey, . . . E Petermann.
J Gen Virol 101:873-883 (2020). Hollingworth R, GS Stewart and RJ Grand. .
Nature 571:521-527 (2019). Daza-Martin M, K Starowicz, M Jamshad, S Tye, GE Ronson, HL MacKay, . . . JR Morris. .
Genes Dev 33:333-347 (2019). Garvin AJ, AK Walker, RM Densham, AS Chauhan, HR Stone, HL Mackay, . . . JR Morris. T.
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. .
Cell Rep 25:2061-2069 e2064 (2018). Bowry A, AL Piberger, P Rojas, M Saponaro and E Petermann. .
Mol Cell 71:25-41 e26 (2018). Higgs MR, K Sato, JJ Reynolds, S Begum, R Bayley, A Goula, . . . GS Stewart..
Nat Commun 9:746 (2018). Ronson GE, AL Piberger, MR Higgs, AL Olsen, GS Stewart, PJ McHugh, . . . E Petermann, ND Lakin. .
Nat Commun 9:229 (2018). Uckelmann M, RM Densham, R Baas, HHK Winterwerp, A Fish, TK Sixma and JR Morris. .
Nature 559:285-289 (2018). Zimmermann M, O Murina, MAM Reijns, A Agathanggelou, R Challis, Z Tarnauskaite, . . . T Stankovic, AP Jackson, D Durocher. s.
Mol Cell 65:900-916 e907 (2017). Clarke TL, MP Sanchez-Bailon, K Chiang, JJ Reynolds, J Herrero-Ruiz, TM Bandeiras, . . . CC Davies. .
J Virol 91 (2017). Campos-Leon K, K Wijendra, A Siddiqa, I Pentland, KM Feeney, A Knapman, . . . JL Parish. .
Cell Rep 21:3498-3513 (2017). Chiang K, AE Zielinska, AM Shaaban, MP Sanchez-Bailon, J Jarrold, TL Clarke, . . . CC Davies. .
Nat Genet 49:537-549 (2017). Reynolds JJ, LS Bicknell, P Carroll, MR Higgs, R Shaheen, JE Murray, . . . GS Stewart. .
Nat Cell Biol 19:468-479 (2017). Sonneville R, SP Moreno, A Knebel, C Johnson, CJ Hastie, A Gartner, . . . K Labib. .
Cell 168:843-855 e813 (2017). Williamson L, M Saponaro, S Boeing, P East, R Mitter, T Kantidakis, . . . JQ Svejstrup. .
Nat Commun 7:13087 (2016). Kotsantis P, LM Silva, S Irmscher, RM Jones, L Folkes, N Gromak and E Petermann. .
PLoS Genet 12:e1005945 (2016). Byrd PJ, GS Stewart, A Smith, C Eaton, AJ Taylor, C Guy, . . . AM Taylor. .
Nat Struct Mol Biol 23:647-655 (2016). Densham RM, AJ Garvin, HR Stone, J Strachan, RA Baldock, M Daza-Martin, . . . JR Morris. .
Nat Genet 48:36-43 (2016). Harley ME, O Murina, A Leitch, MR Higgs, LS Bicknell, G Yigit, . . . AP Jackson. .
Genes Dev 30:408-420 (2016). Kantidakis T, M Saponaro, R Mitter, S Horswell, A Kranz, S Boeing, . . . JQ Svejstrup. .
Blood 127:582-595 (2016). Kwok M, N Davies, A Agathanggelou, E Smith, C Oldreive, E Petermann, . . . T Stankovic..
Dev Cell 38:358-370 (2016). Monteiro R, P Pinheiro, N Joseph, T Peterkin, J Koth, E Repapi, . . . R Patient. .
Mol Cell 59:462-477 (2015). Higgs MR, JJ Reynolds, A Winczura, AN Blackford, V Borel, ES Miller, . . . GS Stewart. .
Science 346:477-481 (2014). Moreno SP, R Bailey, N Campion, S Herron and A Gambus. .
Cell 157:1037-1049 (2014). Saponaro M, T Kantidakis, R Mitter, GP Kelly, M Heron, H Williams, . . . JQ Svejstrup. .
EMBO J 32:1556-1567 (2013). Davies CC, A Chakraborty, ME Diefenbacher, M Skehel and A Behrens. .
EMBO Rep 14:975-983 (2013). Garvin AJ, RM Densham, SA Blair-Reid, KM Pratt, HR Stone, D Weekes, . . . JR Morris.