Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2

Shobbir Hussain, James B. Wilson, Eric Blom, Larry H. Thompson, Patrick Sung, Susan M. Gordon, Gary M. Kupfer, Hans Joenje, Christopher G. Mathew, Nigel J. Jones

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Fanconi anaemia is an inherited chromosomal instability disorder characterised by cellular sensitivity to DNA interstrand crosslinkers, bone-marrow failure and a high risk of cancer. Eleven FA genes have been identified, one of which, FANCD1, is the breast cancer susceptibility gene BRCA2. At least eight FA proteins form a nuclear core complex required for monoubiquitination of FANCD2. The BRCA2/FANCD1 protein is connected to the FA pathway by interactions with the FANCG and FANCD2 proteins, both of which co-localise with the RAD51 recombinase, which is regulated by BRCA2. These connections raise the question of whether any of the FANC proteins of the core complex might also participate in other complexes involved in homologous recombination repair. We therefore tested known FA proteins for direct interaction with RAD51 and its paralogs XRCC2 and XRCC3. FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. FANCG was co-immunoprecipitated with both XRCC3 and BRCA2 from extracts of human and hamster cells. The FANCG-XRCC3 and FANCG-BRCA2 interactions did not require the presence of other FA proteins from the core complex, suggesting that FANCG also participates in a DNA repair complex that is downstream and independent of FANCD2 monoubiquitination. Additionally, XRCC3 and BRCA2 proteins co-precipitate in both human and hamster cells and this interaction requires FANCG. The FANCG protein contains multiple tetratricopeptide repeat motifs (TPRs), which function as scaffolds to mediate protein-protein interactions. Mutation of one or more of these motifs disrupted all of the known interactions of FANCG. We propose that FANCG, in addition to stabilising the FA core complex, may have a role in building multiprotein complexes that facilitate homologous recombination repair.

Original languageEnglish (US)
Pages (from-to)629-640
Number of pages12
JournalDNA Repair
Volume5
Issue number5
DOIs
StatePublished - May 10 2006
Externally publishedYes

Fingerprint

BRCA2 Protein
Genetic Recombination
Fanconi Anemia Complementation Group G Protein
Recombinational DNA Repair
Repair
Proteins
Cricetinae
Fanconi Anemia Complementation Group D2 Protein
Fanconi Anemia Complementation Group Proteins
Genes
Cells
Chromosome Disorders
Fanconi Anemia
Multiprotein Complexes
Chromosomal Instability
Recombinases
Mutation
Neoplasm Genes
DNA
Scaffolds

Keywords

  • BRCA2
  • FANCG
  • Fanconi anaemia
  • Homologous recombination
  • TPR motifs
  • XRCC3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Hussain, S., Wilson, J. B., Blom, E., Thompson, L. H., Sung, P., Gordon, S. M., ... Jones, N. J. (2006). Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2. DNA Repair, 5(5), 629-640. https://doi.org/10.1016/j.dnarep.2006.02.007

Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2. / Hussain, Shobbir; Wilson, James B.; Blom, Eric; Thompson, Larry H.; Sung, Patrick; Gordon, Susan M.; Kupfer, Gary M.; Joenje, Hans; Mathew, Christopher G.; Jones, Nigel J.

In: DNA Repair, Vol. 5, No. 5, 10.05.2006, p. 629-640.

Research output: Contribution to journalArticle

Hussain, S, Wilson, JB, Blom, E, Thompson, LH, Sung, P, Gordon, SM, Kupfer, GM, Joenje, H, Mathew, CG & Jones, NJ 2006, 'Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2', DNA Repair, vol. 5, no. 5, pp. 629-640. https://doi.org/10.1016/j.dnarep.2006.02.007
Hussain, Shobbir ; Wilson, James B. ; Blom, Eric ; Thompson, Larry H. ; Sung, Patrick ; Gordon, Susan M. ; Kupfer, Gary M. ; Joenje, Hans ; Mathew, Christopher G. ; Jones, Nigel J. / Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2. In: DNA Repair. 2006 ; Vol. 5, No. 5. pp. 629-640.
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abstract = "Fanconi anaemia is an inherited chromosomal instability disorder characterised by cellular sensitivity to DNA interstrand crosslinkers, bone-marrow failure and a high risk of cancer. Eleven FA genes have been identified, one of which, FANCD1, is the breast cancer susceptibility gene BRCA2. At least eight FA proteins form a nuclear core complex required for monoubiquitination of FANCD2. The BRCA2/FANCD1 protein is connected to the FA pathway by interactions with the FANCG and FANCD2 proteins, both of which co-localise with the RAD51 recombinase, which is regulated by BRCA2. These connections raise the question of whether any of the FANC proteins of the core complex might also participate in other complexes involved in homologous recombination repair. We therefore tested known FA proteins for direct interaction with RAD51 and its paralogs XRCC2 and XRCC3. FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. FANCG was co-immunoprecipitated with both XRCC3 and BRCA2 from extracts of human and hamster cells. The FANCG-XRCC3 and FANCG-BRCA2 interactions did not require the presence of other FA proteins from the core complex, suggesting that FANCG also participates in a DNA repair complex that is downstream and independent of FANCD2 monoubiquitination. Additionally, XRCC3 and BRCA2 proteins co-precipitate in both human and hamster cells and this interaction requires FANCG. The FANCG protein contains multiple tetratricopeptide repeat motifs (TPRs), which function as scaffolds to mediate protein-protein interactions. Mutation of one or more of these motifs disrupted all of the known interactions of FANCG. We propose that FANCG, in addition to stabilising the FA core complex, may have a role in building multiprotein complexes that facilitate homologous recombination repair.",
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AU - Wilson, James B.

AU - Blom, Eric

AU - Thompson, Larry H.

AU - Sung, Patrick

AU - Gordon, Susan M.

AU - Kupfer, Gary M.

AU - Joenje, Hans

AU - Mathew, Christopher G.

AU - Jones, Nigel J.

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N2 - Fanconi anaemia is an inherited chromosomal instability disorder characterised by cellular sensitivity to DNA interstrand crosslinkers, bone-marrow failure and a high risk of cancer. Eleven FA genes have been identified, one of which, FANCD1, is the breast cancer susceptibility gene BRCA2. At least eight FA proteins form a nuclear core complex required for monoubiquitination of FANCD2. The BRCA2/FANCD1 protein is connected to the FA pathway by interactions with the FANCG and FANCD2 proteins, both of which co-localise with the RAD51 recombinase, which is regulated by BRCA2. These connections raise the question of whether any of the FANC proteins of the core complex might also participate in other complexes involved in homologous recombination repair. We therefore tested known FA proteins for direct interaction with RAD51 and its paralogs XRCC2 and XRCC3. FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. FANCG was co-immunoprecipitated with both XRCC3 and BRCA2 from extracts of human and hamster cells. The FANCG-XRCC3 and FANCG-BRCA2 interactions did not require the presence of other FA proteins from the core complex, suggesting that FANCG also participates in a DNA repair complex that is downstream and independent of FANCD2 monoubiquitination. Additionally, XRCC3 and BRCA2 proteins co-precipitate in both human and hamster cells and this interaction requires FANCG. The FANCG protein contains multiple tetratricopeptide repeat motifs (TPRs), which function as scaffolds to mediate protein-protein interactions. Mutation of one or more of these motifs disrupted all of the known interactions of FANCG. We propose that FANCG, in addition to stabilising the FA core complex, may have a role in building multiprotein complexes that facilitate homologous recombination repair.

AB - Fanconi anaemia is an inherited chromosomal instability disorder characterised by cellular sensitivity to DNA interstrand crosslinkers, bone-marrow failure and a high risk of cancer. Eleven FA genes have been identified, one of which, FANCD1, is the breast cancer susceptibility gene BRCA2. At least eight FA proteins form a nuclear core complex required for monoubiquitination of FANCD2. The BRCA2/FANCD1 protein is connected to the FA pathway by interactions with the FANCG and FANCD2 proteins, both of which co-localise with the RAD51 recombinase, which is regulated by BRCA2. These connections raise the question of whether any of the FANC proteins of the core complex might also participate in other complexes involved in homologous recombination repair. We therefore tested known FA proteins for direct interaction with RAD51 and its paralogs XRCC2 and XRCC3. FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. FANCG was co-immunoprecipitated with both XRCC3 and BRCA2 from extracts of human and hamster cells. The FANCG-XRCC3 and FANCG-BRCA2 interactions did not require the presence of other FA proteins from the core complex, suggesting that FANCG also participates in a DNA repair complex that is downstream and independent of FANCD2 monoubiquitination. Additionally, XRCC3 and BRCA2 proteins co-precipitate in both human and hamster cells and this interaction requires FANCG. The FANCG protein contains multiple tetratricopeptide repeat motifs (TPRs), which function as scaffolds to mediate protein-protein interactions. Mutation of one or more of these motifs disrupted all of the known interactions of FANCG. We propose that FANCG, in addition to stabilising the FA core complex, may have a role in building multiprotein complexes that facilitate homologous recombination repair.

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