Abstract
Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3641-3652 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 27 |
| Issue number | 26 |
| DOIs | |
| State | Published - Jun 12 2008 |
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Keywords
- ATR
- DNA repair
- Epistasis
- Fanconi anemia
- Interstrand crosslinks
- RAD51 paralog
- Replication restart
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. / Wilson, J. B.; Yamamoto, K.; Marriott, A. S.; Hussain, S.; Sung, P.; Hoatlin, Maureen; Mathew, C. G.; Takata, M.; Thompson, L. H.; Kupfer, G. M.; Jones, N. J.
In: Oncogene, Vol. 27, No. 26, 12.06.2008, p. 3641-3652.Research output: Contribution to journal › Article
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TY - JOUR
T1 - FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3
AU - Wilson, J. B.
AU - Yamamoto, K.
AU - Marriott, A. S.
AU - Hussain, S.
AU - Sung, P.
AU - Hoatlin, Maureen
AU - Mathew, C. G.
AU - Takata, M.
AU - Thompson, L. H.
AU - Kupfer, G. M.
AU - Jones, N. J.
PY - 2008/6/12
Y1 - 2008/6/12
N2 - Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.
AB - Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.
KW - ATR
KW - DNA repair
KW - Epistasis
KW - Fanconi anemia
KW - Interstrand crosslinks
KW - RAD51 paralog
KW - Replication restart
UR - http://www.scopus.com/inward/record.url?scp=45949110752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=45949110752&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1211034
DO - 10.1038/sj.onc.1211034
M3 - Article
C2 - 18212739
AN - SCOPUS:45949110752
VL - 27
SP - 3641
EP - 3652
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 26
ER -