Research Topics
Genomes and GenesSpecies | Thomas HelledaySummaryAffiliation: University of Oxford Country: UK Publications
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Publications
Homologous recombination in cancer development, treatment and development of drug resistanceThomas Helleday
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
Carcinogenesis 31:955-60. 2010..Here, I discuss the diversity of HR and how it impacts on cancer with a particular focus on how HR can be exploited in future anticancer strategies...- Amplifying tumour-specific replication lesions by DNA repair inhibitors - a new era in targeted cancer therapyThomas Helleday
Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
Eur J Cancer 44:921-7. 2008..The aim of these therapies is to produce similar lesions to those produced by DNA damaging anti-cancer drugs. The difference is that the lesions will be cancer-specific and produce milder side-effects in non-cancerous cells... - DNA repair pathways as targets for cancer therapyThomas Helleday
Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, off Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
Nat Rev Cancer 8:193-204. 2008.... 
Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase etaNils H Nicolay
Cancer Research UK Medical Research Council Gray Institute for Radiation Oncology and Biology, Oncology Department, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK
Carcinogenesis 33:2026-34. 2012..We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control...- Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cellsPonnari Gottipati
Cancer Research UK Medical Research Council, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom
Cancer Res 70:5389-98. 2010..Furthermore, the presence of PAR polymers can be used to identify HR-defective cells that are sensitive to PARP inhibitors, which may be potential biomarkers... - Transcription-associated recombination in eukaryotes: link between transcription, replication and recombinationPonnari Gottipati
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK
Mutagenesis 24:203-10. 2009..In this review, we aim to present the available evidence for TAR in both lower and higher eukaryotes and discuss its possible mechanisms, with emphasis on its connection with replication... - Chk1 promotes replication fork progression by controlling replication initiationEva Petermann
Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom
Proc Natl Acad Sci U S A 107:16090-5. 2010..Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity... - Targeting homologous recombination repair defects in cancerBastiaan Evers
Gray Institute for Radiation Oncology and Biology, University of Oxford, UK
Trends Pharmacol Sci 31:372-80. 2010..Here we describe recent advances in strategies to identify and target HRD tumours, approaches to overcome resistance, and combinatory strategies to optimize treatment outcome... - Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repairEva Petermann
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
Mol Cell 37:492-502. 2010..In conclusion, our data suggest that restart of stalled replication forks and HR repair of collapsed replication forks require two distinct RAD51-mediated pathways... - Overexpression of POLQ confers a poor prognosis in early breast cancer patientsGeoff S Higgins
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK
Oncotarget 1:175-84. 2010..These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation... - A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdownGeoff S Higgins
Gray Institute for Radiation Oncology and Biology, Oxford University, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
Cancer Res 70:2984-93. 2010..These findings raise the possibility that POLQ inhibition might be used clinically to cause tumor-specific radiosensitization... 
Biological relevance of DNA polymerase β and translesion synthesis polymerases to cancer and its treatmentNils H Nicolay
Cancer Research UK Medical Research Council Gray Institute, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
Curr Mol Pharmacol 5:54-67. 2012..The potential clinical role of new DNA polymerase inhibitors is discussed and how they may be combined with conventional cytotoxic agents...- DNA double-strand break repair: from mechanistic understanding to cancer treatmentThomas Helleday
Radiation Oncology and Biology, University of Oxford, Oxford OX3 7LJ, UK
DNA Repair (Amst) 6:923-35. 2007.... - Transcription-associated recombination is dependent on replication in Mammalian cellsPonnari Gottipati
Radiation Oncology and Biology, Radiobiology Research Institute, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom
Mol Cell Biol 28:154-64. 2008..Furthermore, inhibition of transcription suppresses induction of recombination at stalled replication forks, suggesting that recombination may be involved in bypassing transcription during replication... - XRCC1 phosphorylation by CK2 is required for its stability and efficient DNA repairJason L Parsons
Gray Institute for Radiation Oncology and Biology, University of Oxford, United Kingdom
DNA Repair (Amst) 9:835-41. 2010..We therefore propose that CK2 plays an important role in DNA repair by contributing to the stability of XRCC1-Lig III complex... - Claspin promotes normal replication fork rates in human cellsEva Petermann
Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom
Mol Biol Cell 19:2373-8. 2008..Consistent with this possibility, depletion of Chk1 and Claspin together doubled the percentage of very slow forks, compared with depletion of either protein alone... - The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandingsThomas Helleday
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
Mol Oncol 5:387-93. 2011..Experimental evidence supporting these novel models to explain the PARP-BRCA synthetic lethality are discussed... - Breast cancer stem-like cells show dominant homologous recombination due to a larger S-G2 fractionOsama Al-Assar
Gray Institute for Radiation Oncology and Biology, University of Oxford, Churchill Hospital, UK
Cancer Biol Ther 11:1028-35. 2011..Although the changes we saw were specific to MDA-MB231, these results merit further investigation and can be crucial in identifying a mechanism responsible for cancer stem cells treatment resistance in primary tumors... - Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1Songmin Ying
Gray Institute for Radiation Oncology and Biology, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Cancer Res 72:2814-21. 2012.... - The relationship between homologous recombination repair and the sensitivity of human epidermis to the size of daily doses over a 5-week course of breast radiotherapyNavita Somaiah
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK
Clin Cancer Res 18:5479-88. 2012..Human epidermis was used as a model in which proliferation and DNA repair were correlated over 5 weeks of radiotherapy... - Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cellsChristina Bauerschmidt
CRUK MRC Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, off Roosevelt Drive, Headington, Oxford OX3 7DQ, UK
Exp Cell Res 317:330-7. 2011.... - Mutagenesis: mutating a gene while reading itThomas Helleday
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, OX3 7DQ, UK
Curr Biol 20:R57-8. 2010..Is it possible to mutate DNA during transcription? A new study shows that UV-damaged DNA is deaminated during transcription, which is a probable mechanism underlying CC tandem mutations found in the p53 gene in skin cancers... - The histone methyltransferase SET8 is required for S-phase progressionStine Jørgensen
Biotech Research and Innovation Centre and 2Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen N, Denmark
J Cell Biol 179:1337-45. 2007..Overall, we show that SET8 is essential for genomic stability in mammalian cells and that decreased expression of SET8 results in DNA damage and Chk1-dependent S-phase arrest... - RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cellsKate M Sleeth
The Institute for Cancer Studies, University of Sheffield, Sheffield, UK
J Mol Biol 373:38-47. 2007..Furthermore, our data suggest that replacement of RPA with the RAD51 and RAD52 proteins is affected by checkpoint signalling... - Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpointsJirina Bartkova
Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK 2100 Copenhagen, Denmark
Nature 444:633-7. 2006..Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression... - Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaksCecilia Lundin
Department of Genetics, Microbiology and Toxicology, , S-106 91 Stockholm, Sweden
Nucleic Acids Res 33:3799-811. 2005..We speculate that the reason for recombination-deficient cells being sensitive to MMS is due to the role of HR in repair of MMS-induced stalled replication forks, rather than for repair of cellular DSBs or heat-labile damage... - p53 protects from replication-associated DNA double-strand breaks in mammalian cellsAnuradha Kumari
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Oncogene 23:2324-9. 2004..Altogether, we suggest that the effect of p53 on HR and RAD51 levels and foci can be explained by the idea that p53 suppresses formation of recombinogenic lesions... - RAD51 is involved in repair of damage associated with DNA replication in mammalian cellsCecilia Lundin
Department of Genetic and Cellular Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
J Mol Biol 328:521-35. 2003..This suggests that overexpression of RAD51 prevents long-tract HR occurring during DNA replication. We discuss our results in light of recent models suggested for HR at stalled replication forks... - Pathways for mitotic homologous recombination in mammalian cellsThomas Helleday
Department of Genetic and Cellular Toxicology, Arrhenius Laboratory, Stockholm University, S 106 91 Stockholm, Sweden
Mutat Res 532:103-15. 2003..Recombination repair at a stalled replication fork may occur in the absence of a DSB intermediate and may result in either SCE or gene conversion. Finally, substrates and pathways involved in spontaneous HR are discussed... - Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1Sherif F El-Khamisy
Genome Damage and Stability Centre, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UK
Nature 434:108-13. 2005..These data identify a defect in SSBR in a neurodegenerative disease, and implicate this process in the maintenance of genetic integrity in post-mitotic neurons... - Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapyThomas Helleday
The Institute for Cancer Studies, University of Sheffield, Medical School, Sheffield, UK
Cell Cycle 4:1176-8. 2005..We discuss the recent discoveries on the use of PARP-1 inhibitors as a targeted cancer therapy for recombination deficient cancers, such as BRCA2 tumors... - Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaksNasrollah Saleh-Gohari
Institute for Cancer Studies, University of Sheffield Medical School, UK
Mol Cell Biol 25:7158-69. 2005.... - Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymeraseHelen E Bryant
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Nature 434:913-7. 2005..The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment... - A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forksAtul Mohindra
Institute for Cancer Studies, University of Sheffield, School of Medicine, Sheffield, UK
Hum Mol Genet 13:203-12. 2004..They further suggest a critical role for XRCC2 in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA... - Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombinationNiklas Schultz
Department of Genetic and Cellular Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
Nucleic Acids Res 31:4959-64. 2003..Our data suggest that PARP-1 controls DNA damage recognised by HR and that it is not involved in executing HR as such... - Caffeine delays replication fork progression and enhances UV-induced homologous recombination in Chinese hamster cell linesFredrik Johansson
Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratories for the Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden
DNA Repair (Amst) 5:1449-58. 2006..The biological consequence of the former pathway is mutations, while the latter results in chromosomal aberrations... - The role of RAD51 in etoposide (VP16) resistance in small cell lung cancerLasse Tengbjerg Hansen
Institute of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark
Int J Cancer 105:472-9. 2003..Finally, we propose RAD51 as a potential target to improve VP16 efficacy and predict tumor resistance in the treatment of SCLC patients... - DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancerLasse Tengbjerg Hansen
Institute of Molecular Pathology, University of Copenhagen, Frederik V s vej 11, 5 sal, DK 2100 Copenhagen, Denmark
Lung Cancer 40:157-64. 2003.... - Defects in homologous recombination repair in mismatch-repair-deficient tumour cell linesAtul Mohindra
Institute for Cancer Studies, University of Sheffield School of Medicine, Beech Hill Road, UK
Hum Mol Genet 11:2189-200. 2002..The increased thymidine sensitivity and the loss of an important pathway for the repair of DNA double-strand breaks create new opportunities for therapies directed specifically against this subset of tumours... - Overexpression of cyclin E does not influence homologous recombination in Chinese hamster cellsCecilia Lundin
Department of Genetic and Cellular Toxicology, Stockholm University, Stockholm, Sweden
Biochem Biophys Res Commun 296:363-7. 2002..Our data suggest that genetic instability caused by overexpression of cyclin E is not mediated by aberrant homologous recombination... - Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cellsNasrollah Saleh-Gohari
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Nucleic Acids Res 32:3683-8. 2004..This indicates that the same pathway for conservative HR is employed in the repair of DSBs regardless of phase of the cell cycle and that only the frequency is affected... - Screening for genotoxicity using the DRAG assay: investigation of halogenated environmental contaminantsFredrik Johansson
Department of Genetics, Microbiology and Toxicology, Stockholm University, SE-106 91, Sweden
Mutat Res 563:35-47. 2004..However, the usefulness of the selected cell lines to detect oxidative damage may be limited... - ATM is required for the cellular response to thymidine induced replication fork stressEmma Bolderson
Institute for Cancer Studies, School of Medicine, University of Sheffield, UK
Hum Mol Genet 13:2937-45. 2004..Taken together, our results implicate ATM in the HRR-mediated rescue of replication forks impaired by thymidine treatment... - Homologous recombination is involved in repair of chromium-induced DNA damage in mammalian cellsHelen E Bryant
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Mutat Res 599:116-23. 2006..In addition, we find that ERCC1, XRCC1 and DNA-PKcs defective cells are hypersensitive to Cr[VI], indicating that several repair pathways cooperate in repairing Cr[VI]-induced DNA damage... - RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repairAlihossein Saberi
CREST Research Project, Radiation Genetics, Faculty of Medicine, Kyoto University, Sakyo ku, Kyoto 606 8501, Japan
Mol Cell Biol 27:2562-71. 2007..In conclusion, higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks... - Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repairHelen E Bryant
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Nucleic Acids Res 34:1685-91. 2006..Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs)... - Mitotic defects in XRCC3 variants T241M and D213N and their relation to cancer susceptibilityAnna Renglin Lindh
Departmen tof Genetics, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden
Hum Mol Genet 15:1217-24. 2006..In contrast, cells carrying the XRCC3 D213N variant are able to eliminate aberrant cells by apoptosis, and consistent with this observation, this variant does not seem to be associated with cancer susceptibility... - The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cellsAli Z Al-Minawi
Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Nucleic Acids Res 36:1-9. 2008..Furthermore, we find that SSA is not influenced by inhibition of CDK2 (using Roscovitine), ATM (using Caffeine and KU55933), Chk1 (using CEP-3891) or DNA-PK (using NU7026)... - Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakageRandi G Syljuåsen
Institute of Cancer Biology, Department of Cell Cycle and Cancer, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark
Mol Cell Biol 25:3553-62. 2005..These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment... - The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repairClaus Storgaard Sørensen
Danish Cancer Society, Institute of Cancer Biology, DK 2100 Copenhagen, Denmark
Nat Cell Biol 7:195-201. 2005..These results highlight a crucial role for the Chk1 signalling pathway in protecting cells against lethal DNA lesions through regulation of HRR... - Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesisClarisse Bavoux
Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique, Toulouse, France
Cancer Res 65:325-30. 2005..These data suggest that altered regulation of DNA metabolism might be related to cancer-associated genetic changes and phenotype... - Strand invasion involving short tract gene conversion is specifically suppressed in BRCA2-deficient hamster cellsNasrollah Saleh-Gohari
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Oncogene 23:9136-41. 2004..These data suggest that BRCA2-defective hamster cells are impaired in short tract gene conversion but maintain proficiency in sister chromatid exchange... - Different roles for nonhomologous end joining and homologous recombination following replication arrest in mammalian cellsCecilia Lundin
Department of Genetic and Cellular Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
Mol Cell Biol 22:5869-78. 2002..Our data suggest that both NHEJ and HR are involved in repair of arrested replication forks that include a DSB, while HR alone is required for the repair of slowed replication forks in the absence of detectable DSBs...