Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene

Jung Young Park, Elizabeth L. Virts, Anna Jankowska, Constanze Wiek, Mohamed Othman, Sujata C. Chakraborty, Gail Vance, Fowzan S. Alkuraya, Helmut Hanenberg, Paul R. Andreassen

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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 wildtype 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.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - May 20 2016

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Fanconi Anemia
Hypersensitivity
DNA
Genes
Phenotype
Mutation
Bone Marrow
Chromosome Breakage
Mitomycin
Ionizing Radiation
DNA Repair
Formaldehyde
Cell Cycle

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Park, J. Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., ... Andreassen, P. R. (Accepted/In press). Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-103847

Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. / Park, Jung Young; Virts, Elizabeth L.; Jankowska, Anna; Wiek, Constanze; Othman, Mohamed; Chakraborty, Sujata C.; Vance, Gail; Alkuraya, Fowzan S.; Hanenberg, Helmut; Andreassen, Paul R.

In: Journal of Medical Genetics, 20.05.2016.

Research output: Contribution to journalArticle

Park, Jung Young ; Virts, Elizabeth L. ; Jankowska, Anna ; Wiek, Constanze ; Othman, Mohamed ; Chakraborty, Sujata C. ; Vance, Gail ; Alkuraya, Fowzan S. ; Hanenberg, Helmut ; Andreassen, Paul R. / Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. In: Journal of Medical Genetics. 2016.
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title = "Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene",
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 wildtype 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.",
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T1 - Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene

AU - Park, Jung Young

AU - Virts, Elizabeth L.

AU - Jankowska, Anna

AU - Wiek, Constanze

AU - Othman, Mohamed

AU - Chakraborty, Sujata C.

AU - Vance, Gail

AU - Alkuraya, Fowzan S.

AU - Hanenberg, Helmut

AU - Andreassen, Paul R.

PY - 2016/5/20

Y1 - 2016/5/20

N2 - 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 wildtype 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.

AB - 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 wildtype 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.

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