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Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene
  1. Jung-Young Park1,
  2. Elizabeth L Virts2,
  3. Anna Jankowska2,
  4. Constanze Wiek3,
  5. Mohamed Othman4,
  6. Sujata C Chakraborty5,
  7. Gail H Vance5,
  8. Fowzan S Alkuraya6,7,
  9. Helmut Hanenberg2,3,8,
  10. Paul R Andreassen1,9
  1. 1Division of Experimental Hematology & Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Wells Center for Pediatric Research, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA
  3. 3Department of Otorhinolaryngology & Head/Neck Surgery, Heinrich Heine University Duesseldorf, Duesseldorf, Germany
  4. 4Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  5. 5Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
  6. 6Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  7. 7Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  8. 8Department of Pediatrics III, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany
  9. 9Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  1. Correspondence to Dr Helmut Hanenberg, Department of Pediatrics III, University Children's Hospital Essen, University Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany; Helmut.Hanenberg{at}uk-essen.de Dr Paul R Andreassen, Division of Experimental Hematology & Cancer Biology, Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., ML S7.203, Cincinnati OH 45229, USA; Paul.Andreassen{at}cchmc.org

Abstract

Background Fanconi anaemia (FA) is a heterogeneous inherited disorder clinically characterised by progressive bone marrow failure, congenital anomalies and a predisposition to malignancies.

Objective Determine, based on correction of cellular phenotypes, whether XRCC2 is a FA gene.

Methods Cells (900677A) from a previously identified patient with biallelic mutation of XRCC2, among other mutations, were genetically complemented with wild-type XRCC2.

Results Wild-type XRCC2 corrects each of three phenotypes characteristic of FA cells, all related to the repair of DNA interstrand crosslinks, including increased sensitivity to mitomycin C (MMC), chromosome breakage and G2–M accumulation in the cell cycle. Further, the p.R215X mutant of XRCC2, which is harboured by the patient, is unstable. This provides an explanation for the pathogenesis of this mutant, as does the fact that 900677A cells have reduced levels of other proteins in the XRCC2–RAD51B-C-D complex. Also, FANCD2 monoubiquitination and foci formation, but not assembly of RAD51 foci, are normal in 900677A cells. Thus, XRCC2 acts late in the FA–BRCA pathway as also suggested by hypersensitivity of 900677A cells to ionising radiation. These cells also share milder sensitivities towards olaparib and formaldehyde with certain other FA cells.

Conclusions XRCC2/FANCU is a FA gene, as is another RAD51 paralog gene, RAD51C/FANCO. Notably, similar to a subset of FA genes that act downstream of FANCD2, biallelic mutation of XRCC2/FANCU has not been associated with bone marrow failure. Taken together, our results yield important insights into phenotypes related to FA and its genetic origins.

  • Fanconi anemia
  • XRCC2
  • RAD51 paralogs
  • DNA interstrand crosslinks
  • Breast cancer susceptibility

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