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Bi-allelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics
  1. Julian Barwell (julian.barwell{at}stgeorges.nhs.uk)
  1. St George Medical School, Genetics, United Kingdom
    1. Laurent Pangon (pangonlaurent{at}hotmail.com)
    1. Guy's hospital , Medical and molecular genetics, United Kingdom
      1. Shirley Hodgson (shirley.hodgson{at}stgeorges.nhs.uk)
      1. St George Medical School, Genetics, United Kingdom
        1. Anne Georgiou (anne.georgiou{at}genetics.kcl.ac.uk)
        1. Guy's Hospital, Cytogenetics, United Kingdom
          1. Ian Kesterton (ian.kesterton{at}gstt.nhs.uk)
          1. Guy's Hospital, Cytogenetics, United Kingdom
            1. Tina Slade (tina.slade{at}gstt.nhs.uk)
            1. Guy's Hospital, Biochemical Genetics, United Kingdom
              1. Michelle Taylor (m.taylor{at}imperial.ac.uk)
              1. Kennedy-Galton Centre, NW Thames Regional Genetics Service, United Kingdom
                1. Stewart J. Payne (s.j.payne{at}imperial.ac.uk)
                1. Kennedy-Galton Centre, NW Thames Regional Genetics Service, United Kingdom
                  1. Heike Brinkman (hb2{at}sanger.ac.uk)
                  1. Welcome Trust sanger Institute, United Kingdom
                    1. Jon Smythe (jon.smythe{at}nbs.nhs.uk)
                    1. National Blood service, Stem cell and Immunotherapy, United Kingdom
                      1. Neil J. Sebire (sebirn{at}gosh.nhs.uk)
                      1. Camelia Botnar Laboratories, Paediatric Pathology, United Kingdom
                        1. Ellen Solomon (ellen.solomon{at}genetics.kcl.ac.uk)
                        1. Guy's Hospital, Medical and Molecular Genetics, United Kingdom
                          1. Zoe Docherty (zoe.docherty{at}gstt.nhs.uk)
                          1. Guy's Hospital, Cytogenetics, United Kingdom
                            1. Richard Camplejohn (r.camplejohn{at}cancer.org.uk)
                            1. KCL School of Medecine, Oncology, United Kingdom
                              1. Tessa Homfray (thomfray{at}sgul.ac.uk)
                              1. St George Medical School, Genetics, United Kingdom
                                1. Joanna R. Morris (jo.morris{at}genetics.kcl.ac.uk)
                                1. Guy's Hospital, Medical and Molecular Genetics, United Kingdom

                                  Abstract

                                  Background: Reports of differential mutagen sensitivity conferred by a defect in the mismatch repair (MMR) pathway are inconsistent in their conclusions. Previous studies have investigated cells established from immortalized human colorectal tumor lines or cells from animal models.

                                  Methods: We examined primary human MSH2-deficient neonatal cells, bearing a bi-allelic truncating mutation in MSH2 for viability and chromosomal damage following exposure to DNA damaging agents.

                                  Results: MSH2 deficient cells exhibit no response to interstrand DNA cross-linking agents but do show reduced viability in response to irradiation. They also show increased chromosome damage and exhibit altered RAD51 foci kinetics following irradiation exposure, indicating defective homologous recombinational repair.

                                  Discussion: The cellular features and sensitivity of MSH2 deficient primary human cells are broadly in agreement with observations of primary murine cells lacking the same gene. The data therefore support the view that the murine model recapitulates early features of mismatch repair deficiency in humans and implies that the variable data reported for MMR deficient immortalised human cells may be due to further genetic or epigenetic lesions. We suggest caution in the use of radiotherapy for treatment of malignancies in individuals with functional loss of MSH2.

                                  • RAD51
                                  • homozygous MSH2 deficiency
                                  • irradiation
                                  • mismatch repair
                                  • primary cells

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