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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-01-0278.
HEMATOPOIESIS
From the Department of Pediatric Oncology, Dana-Farber
Cancer Institute, Harvard Medical School, Boston, MA; the Department of
Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA;
and the Department of Molecular and Medical Genetics and Department of
Pediatrics, Oregon Health Sciences University, Portland.
Fanconi anemia (FA) is a human autosomal recessive cancer
susceptibility disorder characterized by cellular sensitivity to mitomycin C and defective cell-cycle progression. Six FA genes (corresponding to subtypes A, C, D2, E, F, and G) have been cloned, and
the encoded FA proteins interact in a common pathway. DNA damage
activates this pathway, leading to monoubiquitination of the downstream
FANCD2 protein and targeting to nuclear foci containing BRCA1. In the
current study, we demonstrate that FANCD2 also undergoes monoubiquitination during S phase of the cell cycle. Monoubiquitinated FANCD2 colocalizes with BRCA1 and RAD51 in S-phase-specific nuclear foci. Monoubiquitination of FANCD2 is required for normal cell-cycle progression following cellular exposure to mitomycin C. Our data indicate that the monoubiquitination of FANCD2 is highly regulated, and
they suggest that FANCD2/BRCA1 complexes and FANCD2/RAD51 complexes
participate in an S-phase-specific cellular process, such as DNA
repair by homologous recombination.
(Blood. 2002;100:2414-2420) Fanconi anemia (FA) is an autosomal recessive
cancer susceptibility syndrome characterized by multiple congenital
anomalies and progressive bone marrow failure.1,2 FA cells
are sensitive to DNA cross-linking agents, such as mitomycin C (MMC)
and, to a lesser extent, ionizing radiation (IR).3,4 Based
on somatic cell fusion studies, FA is composed of 8 distinct
complementation groups (A, B, C, D1, D2, E, F, and
G).5,6 Six of the FA genes Recent studies have demonstrated that the 6 cloned FA proteins interact
in a common cellular pathway.13 The FANCA, FANCC, FANCE,
FANCF, and FANCG proteins assemble in a multisubunit nuclear complex.14,15 This FA protein complex is required
for the monoubiquitination of the FANCD2 protein, suggesting that the
complex functions as a multisubunit monoubiquitin ligase or regulates
such an activity. When normal (non-FA) cells are exposed to
DNA-damaging agents, FANCD2 is monoubiquitinated and targeted to
nuclear foci containing BRCA1.13 Disruption of this
pathway leads to the characteristic cellular and clinical abnormalities
observed in FA.
FA cells have a defect in cell-cycle progression. First, FA cells lack
the ability to delay S-phase progression in response to DNA damage from
DNA cross-linking agents.16,17 Second, FA cells accumulate
in the G2 phase of the cell cycle following cross-linker exposure.18 This G2 delay appears to result
from a normal G2/M checkpoint response to excessive DNA
damage in the preceding S phase.19 Third, recent studies
demonstrate that FA cells arrest in late S phase following cellular
exposure to interstrand cross-links (ICLs), suggesting that the FA
pathway helps to repair these cross-links in S phase.20,21
The recently demonstrated interaction between FANCD2 and
BRCA113 has suggested possible cellular functions of the
FA pathway. BRCA1( In the current study, we examined the FANCD2 protein during the cell
cycle. We found that FANCD2 is monoubiquitinated during the S phase of
the cell cycle and that FANCD2/BRCA1 foci and FANCD2/RAD51 foci form
during S phase. The monoubiquitination of FANCD2 during S phase is
required for normal cell-cycle progression following cellular exposure
to MMC.
Cell lines and culture conditions
Retroviral infection and MMC sensitivity assay
Cell-cycle synchronization HeLa cells or the indicated FA fibroblast lines were synchronized by the double-thymidine-block method as previously described, with minor modifications.27 Briefly, cells were treated with 2 mM thymidine for 18 hours, thymidine-free media for 10 hours, and 2 mM thymidine for 18 hours to arrest the cell cycle at the G1/S boundary. Cells were washed twice with phosphate-buffered saline (PBS) and then released in DMEM + 15% FCS and analyzed at various time intervals. Alternatively, HeLa cells were treated with 0.5 mM mimosine (Sigma, St Louis, MO) for 24 hours for synchronization in late G1 phase,28 washed twice with PBS, and released into DMEM + 15% FCS. For synchronization in M phase, a nocodazole block was used.29 Cells were treated with 0.1 µg/mL nocodazole (Sigma) for 15 hours, and the nonadherent cells were washed twice with PBS and replated in DMEM + 15% FCS.Cell-cycle analysis Trypsinized cells were resuspended in 0.5 mL PBS and fixed by adding 5 mL ice-cold ethanol. Cells were next washed twice with PBS with 1% bovine serum albumin (BSA) fraction V (1% BSA/PBS; Sigma) and were resuspended in 0.24 mL of 1% BSA/PBS. After adding 30 µL of 500 µg/mL propidium iodide (Sigma) in 38 mM sodium citrate (pH 7.0) and 30 µL of 10 mg/mL DNase-free RNase A (Sigma), samples were incubated at 37°C for 30 minutes. DNA content was measured by FACScan (Becton Dickinson, San Jose, CA), and data were analyzed by the CellQuest and Modfit LT programs (Becton Dickinson).Determination of the G2 to M cell-cycle transition PD20 cell lines were synchronized at the G1/S interface as described above, except that 10 mM thymidine treatment was used. Treatment with 500 nM (167 ng/mL) MMC was from 1 to 3 hours following release from the second thymidine block. At the indicated time points, cells were collected by trypsinization, pooled with nonattached cells, and fixed for a minimum of 10 minutes with 90% methanol/PBS at 20°C. Cells were then washed with PBS, incubated
for 1 hour at 37°C with a 200-fold dilution of MPM-2 antibody (DAKO,
Carpinteria, CA) in antibody buffer (PBS containing 3% BSA, 0.05%
Tween-20, and 0.04% sodium azide). Cells were washed once with PBS and
were incubated with a 500-fold dilution of fluorescein-conjugated
antimouse immunoglobulin G (IgG) secondary antibodies in antibody
buffer for 30 minutes at 37°C. Cells were washed once with PBS and
then were incubated for 10 minutes at 37°C in 4 mM sodium citrate (pH 7.8), 1% triton X-100, 30 U/mL DNase-free RNase A, and 50 mg/mL propidium iodide. Following the addition of NaCl to 138 mM, cells were
kept on ice until analyzed with a FACScan system using Cell Quest
Software (Becton Dickinson). Cell aggregates were gated out, and
10 000 events were analyzed.
Immunoblotting Immunoblotting was performed as previously described.13 Anti-FANCD2 mouse monoclonal antibody FI17 (1:200 dilution) was used as a primary antibody.Immunofluorescence microscopy Cells were fixed with 2% paraformaldehyde in PBS for 20 minutes, followed by permeabilization with 0.3% Triton-X-100 in PBS (10 minutes). After blocking in 10% goat serum and 0.1% NP-40 in PBS (blocking buffer), specific antibodies were added at the appropriate dilution in blocking buffer and were incubated for 2 to 4 hours at room temperature. FANCD2 was detected using the affinity-purified E35 polyclonal antibody (1/100).13 For BRCA1 detection, we used a commercial monoclonal antibody (D-9; Santa Cruz Biotechnology, CA) at 2 µg/mL. For HA detection, anti-HA (HA.11; Babco, Richmond, CA) (1:500) antibody was used. Alternatively, the polyclonal anti-RAD51 antibody (Oncogene, Boston, MA; Ab-1, 1:800) was used. Cells were subsequently washed 3 times in PBS + 0.1% NP-40 (10-15 minutes each wash), and species-specific fluorescein or Texas red-conjugated secondary antibodies (Jackson Immunoresearch, West Grove, PA) were diluted in blocking buffer (antimouse 1/700, antirabbit 1/700) and added. After 1 hour at room temperature, 3 more 10- to 15-minute washes containing 1 µg/mL DAPI were applied, and the slides were mounted in Vectashield (Vector Laboratories, Burlingame, CA). Images were captured on a Nikon microscope and processed using Openlab (Improvision, Lexington, MA) and Adobe Photoshop software. Colocalization of FANCD2 and BRCA1 was performed as previously described.13
FANCD2 is monoubiquitinated during S phase We initially examined the activation of the FA pathway during normal cell-cycle progression in the absence of DNA-damaging agents (Figure 1). HeLa cells were synchronized at the G1/S boundary by double-thymidine block, released into S phase, and analyzed for the presence of FANCD2 by immunoblotting (Figure 1A). FANCD2-L (monoubiquitinated isoform) was detected specifically at the G1/S boundary and throughout the S phase. S-phase detection of FANCD2-L was confirmed when HeLa cells were synchronized by other methods, such as nocodazole arrest (Figure 1B) or mimosine block (Figure 1C). Cells arrested in mitosis did not display FANCD2-L, suggesting that FANCD2-L is deubiquitinated or degraded before cell division (Figure 1A, 10 hours). These results demonstrate that FANCD2 monoubiquitination is highly regulated during the cell cycle.
We next demonstrated that the cell-cycle-dependent monoubiquitination of FANCD2 correlated with the formation of FANCD2 nuclear foci (Figure 1D). Nocodazole arrested (mitotic) cells exhibited no FANCD2 foci (Figure 1D, panel ii). During G1 phase (6 hours after release from synchronization with nocodazole), only FANCD2-S was detected by immunoblotting, and this protein was distributed in a diffuse nuclear pattern (Figure 1D, panel iii). When the synchronized cells entered S phase (15 to 18 hours), an increase in FANCD2-L and FANCD2 nuclear foci was observed (Figure 1D, panels vi,vii). A similar result was observed in mimosine-synchronized cells (Figure 1E). We have previously shown that FA cells from complementation groups A,
C, F, and G fail to assemble the FA protein complex and fail to
monoubiquitinate FANCD2 in response to DNA damage.13 We
examined the expression of the FANCD2 isoforms in FA cells and
functionally complemented FA cells during the cell cycle (Figure 2). FA-A cells showed normal levels of
FANCD2-S throughout the cell cycle but failed to display
monoubiquitinated FANCD2-L at any point during the cell cycle (Figure
2A). Functional complementation of these cells by stable transfection
with the FANCA cDNA restored MMC resistance25 and restored
the S-phase-specific expression of FANCD2-L. Similar results were
obtained when the FA-A and corrected FA-A cells were synchronized with
nocodazole (Figure 2B).
Monoubiquitination of FANCD2 at K561 during S phase is required for normal cell-cycle progression We next examined whether the S-phase-dependent expression of FANCD2-L results from monoubiquitination at lysine 561 (Lys561) (Figure 3). FA-D2 (PD20) fibroblasts, devoid of FANCD2 protein, were stably transduced with the cDNA encoding either FANCD2 (wt) or FANCD2 (K561R). Expression of wild-type FANCD2, but not FANCD2 (K561R), corrected the MMC sensitivity of the FA-D2 cells, as previously described (data not shown).13 The corrected cells demonstrated S-phase-specific monoubiquitination of FANCD2 (Figure 3A). In contrast, FANCD2 (K561R) was not monoubiquitinated during the cell cycle.
We next analyzed cell-cycle progression in the various transfected
FA-D2 fibroblast lines (Table 1 and
Figure 3B). Double-thymidine-blocked cells were released into S phase,
either in the absence or presence of the DNA cross-linking agent MMC,
and were analyzed for cell-cycle progression. By 3 hours following
release, cells had advanced into S phase to more than 85%,
irrespective of MMC exposure. Uncorrected FA-D2 cells (ie, transduced
with empty vector or with the cDNA-encoding FANCD2 [K561R]) and
corrected FA cells (ie, transduced with the wild-type FANCD2 cDNA)
showed no difference in S-phase duration (Table 1). More than 77% of
the synchronized cells had traversed S phase and entered
G2/M phase after 8 hours. Exposure to MMC had no obvious
effect on S-phase duration (8 hours). By 12 hours following release
from double-thymidine block, in the absence of MMC, many corrected and
uncorrected PD20 cells had completed cell division as determined by the
reappearance of a G1 peak. However, MMC-exposed cells
retained a 4 N DNA content longer and failed to progress to the
G1 phase of the next cell cycle.
To determine whether the 4 N arrest following MMC occurred in G2 versus M phase, we used a biparameter flow cytometric assay with MPM-2 antibody (specific for mitotic-phosphorylated protein) and DNA content (Figure 3B).30,31 Cells with 4 N DNA content and high expression of MPM-2 were scored as mitotic cells. In the absence of MMC-induced DNA damage, there was no significant difference in the progression of corrected or uncorrected FA cells from G2 to M phase. The peak in mitosis occurred at 10 to 12 hours after release from G1/S block. In the presence of MMC-induced DNA damage, entry into mitosis was strongly suppressed in FANCD2 (wt)-corrected FA-D2 cells. Mitotic entry in uncorrected (empty vector-transfected or FANCD2 [K561R]-transfected) cells was strongly suppressed, with the peak of mitosis occurring more than 15 hours after release from G1/S. Taken together, these results demonstrate that uncorrected FA cells have a prolonged G2 to M transit time following cross-linker exposure. BRCA1 colocalizes with FANCD2 during S phase Because FANCD2 colocalizes with BRCA1 following DNA damage, we next tested whether FANCD2 colocalizes with BRCA1 during S phase in the absence of DNA-damaging agents (Figure 4). HeLa cells were synchronized with mimosine, released into S phase, and costained with antisera to FANCD2 and BRCA1. As shown in Figure 4A, during S phase most (70%) FANCD2 foci overlapped with BRCA1 foci.
We examined the dynamic behavior of FANCD2 and BRCA1 foci in S phase following DNA damage (Figure 4B). Treatment of S-phase-synchronized cells with IR, MMC, or UV resulted in a rapid diffusion of BRCA1 dots, as previously described.32,33 FANCD2 dots did not disperse following DNA damage, suggesting that BRCA1 and FANCD2 proteins transiently dissociate in response to DNA damage. The FANCD2 protein is therefore similar to other BRCA1-associated proteins, such as hCds1/Chk233 and CtIP,34 which transiently dissociate from BRCA1 foci following IR-activated BRCA1 phosphorylation in S phase. Interaction of FANCD2 and RAD51 during S phase The RecA homologue, RAD51, binds single-stranded DNA and, together with BRCA2, is required for homology-directed DNA repair.35 RAD51 forms nuclear foci during S phase in untreated cells and colocalizes with BRCA1 in ionizing-radiation-inducible foci and in S-phase foci.36 We therefore determined whether the activated (monoubiquitinated) FANCD2 protein colocalizes with RAD51 by performing double immunolabeling in complemented FANCD2 cells (Figure 5). PD20 (FA-D2) fibroblasts cells were stably transfected and complemented with an amino terminal epitope (HA)-tagged form of FANCD2 (Figure 5A). Immunofluorescence revealed that the HA-FANCD2 colocalizes with endogenous RAD51 during S phase (Figure 5B). The interaction of FANCD2 and RAD51 further supports a model in which FANCD2 functions in homologous recombination repair during S phase.
In the current study, we demonstrate that the FA pathway is activated during S phase of the normal cell cycle. Like DNA damage-inducible monoubiquitination, the S-phase-specific monoubiquitination of FANCD2 is dependent on the presence of an intact FA protein complex. FANCD2 monoubiquitination is required for normal cell-cycle progression following DNA damage. FA-D2 cells and corrected FA-D2 cells traverse S phase with similar kinetics. If the cells are exposed to DNA cross-linkers during S phase, however, the mutant (noncorrected) cells fail to progress from G2 to M. The monoubiquitination of FANCD2 during S phase is required for the normal completion of the subsequent phases of the cell cycle. Regulation of S-phase-specific monoubiquitination The molecular events that regulate the S-phase-specific monoubiquitination of FANCD2 are unknown, and several models are possible. First, the FA protein complex may become an active monoubiquitin ligase during S phase. For instance, a protein subunit of the complex may become activated by phosphorylation during S phase. Alternatively, the FA complex may assemble or may acquire new active subunits during S phase, resulting in its activation. At least one subunit (FANCG) of the FA protein complex is cyclically phosphorylated in mitosis,37 suggesting a possible mechanism of cell-cycle-dependent modulation of enzyme activity. Second, the FANCD2 protein may become phosphorylated during S phase, rendering it a suitable substrate for monoubiquitination. Consistent with this latter model, the FANCD2 protein is a phosphoprotein, though its specific kinase(s) remain unknown (data not shown).S-phase-specific monoubiquitination and DNA damage-inducible monoubiquitination of FANCD2 appear to be mechanistically distinct. For instance, DNA damage activates FANCD2 monoubiquitination and FANCD2 foci formation even during the G1 phase of the cell cycle (I.G.-H., unpublished observation, December 2000). Perhaps different upstream kinases activate S-phase- or DNA-damage-inducible monoubiquitination. Like FANCD2, BRCA1 is phosphorylated in S phase or following cellular exposure to DNA damage. Cyclin A/cdk2 activates cell-cycle-dependent phosphorylation of BRCA1,29 and ATM, ATR, and CHK2 activate the DNA damage-inducible phosphorylation of BRCA1.33,38-40 Phosphorylation of BRCA1, resulting from IR induction or S-phase progression, may enhance ubiquitin ligase activity and monoubiquitination of FANCD2. Consistent with this model, recent studies have shown that ATM-dependent phosphorylation of another ubiquitin ligase, MDM2, may regulate its ability to ubiquitinate p53.41 As cells enter G2/M, the monoubiquitinated FANCD2-L isoform is no longer detected, suggesting that it is either deubiquitinated or degraded at this stage of the cell cycle. Deubiquitination is more likely than degradation, because there is no obvious change in the steady state level of FANCD2 protein during cell-cycle progression and the protein half-life of the wild-type and K561R (unubiquitinated) FANCD2 polypeptides are similar (data not shown). Identification of the deubiquitinating enzyme, which converts FANCD2-L to FANCD2-S, may reveal an important level of regulation of the FA pathway. Possible functional roles of FANCD2/BRCA1 foci and FANCD2/RAD51 foci in S phase Recent studies have demonstrated that the BRCA1 protein is required for HDR.22,24 One type of HDR (ie, gene conversion by sister chromatids) can occur during S phase of the cell cycle.42,43 Gene conversion occurs during normal DNA replication42 and may function to repair replication intermediates (ie, double-strand breaks) that occur normally during S phase. HDR is an error-free mechanism of DNA repair, requires DNA replication and strand invasion by a sister chromatid, and requires RAD51. Consistent with a direct role in homologous recombination, BRCA1 forms foci with RAD51 during normal S phase.36Several lines of evidence support the notion that FANCD2 interacts with
BRCA1 and RAD51 in an S-phase DNA repair or checkpoint response. First,
BRCA1 protein and FANCD2 protein are not expressed in G0 (resting)
cells, and levels are induced following cell stimulation with serum
(data not shown). Second, BRCA1 is phosphorylated during S phase and
forms foci in S phase, consistent with a specific S-phase
function.32 Third, recent studies have shown that
BRCA1( Because FANCD2 interacts with BRCA1 and RAD51 during S phase and because cellular deficiency of either FANCD2 or BRCA1 results in severe MMC sensitivity, disruption of the FA pathway may also disrupt HDR activity. We are currently testing this hypothesis. In a normal cell, the FA pathway may function by regulating the magnitude or fidelity of DNA repair by homologous recombination. Finally, an understanding of the precise role of activated FANCD2 in DNA repair may require the identification of other FANCD2-binding proteins or the establishment of in vitro models of repair by homologous recombination.
Submitted January 30, 2002; accepted April 5, 2002.
Prepublished online as Blood First Edition Paper, June 28, 2002; DOI 10.1182/blood-2002-01-0278.
Supported by National Institutes of Health grants RO1HL52725-04, RO1DK43889-09, PO1HL54785-04, PO1DK5654 (A.D.D.), and F32-CA88445-01 (R.C.G.) and by a grant from the Naito Foundation (T.T.). I.G.-H. and P.R.A. are Special Fellows of the Leukemia and Lymphoma Society.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alan D. D'Andrea, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: alan_dandrea{at}dfci.harvard.edu.
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© 2002 by The American Society of Hematology.
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  T. R. Singh, S. T. Bakker, S. Agarwal, M. Jansen, E. Grassman, B. C. Godthelp, A. M. Ali, C.-h. Du, M. A. Rooimans, Q. Fan, et al. Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M Blood, July 2, 2009; 114(1): 174 - 180. [Abstract] [Full Text] [PDF]
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 Q. Fan, F. Zhang, B. Barrett, K. Ren, and P. R. Andreassen A role for monoubiquitinated FANCD2 at telomeres in ALT cells Nucleic Acids Res., April 1, 2009; 37(6): 1740 - 1754. [Abstract] [Full Text] [PDF]
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N. B. Collins, J. B. Wilson, T. Bush, A. Thomashevski, K. J. Roberts, N. J. Jones, and G. M. Kupfer ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function Blood, March 5, 2009; 113(10): 2181 - 2190. [Abstract] [Full Text] [PDF]
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 Y. Kee, J. M. Kim, and A. D'Andrea Regulated degradation of FANCM in the Fanconi anemia pathway during mitosis Genes & Dev., March 1, 2009; 23(5): 555 - 560. [Abstract] [Full Text] [PDF]
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Y. Si, A. C. Pulliam, Y. Linka, S. Ciccone, C. Leurs, J. Yuan, O. Eckermann, S. Fruehauf, S. Mooney, H. Hanenberg, et al. Overnight transduction with foamyviral vectors restores the long-term repopulating activity of Fancc-/- stem cells Blood, December 1, 2008; 112(12): 4458 - 4465. [Abstract] [Full Text] [PDF]
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J. M. Kim, Y. Kee, A. Gurtan, and A. D. D'Andrea Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24 Blood, May 15, 2008; 111(10): 5215 - 5222. [Abstract] [Full Text] [PDF]
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 J. L. Youds, L. J. Barber, J. D. Ward, S. J. Collis, N. J. O'Neil, S. J. Boulton, and A. M. Rose DOG-1 Is the Caenorhabditis elegans BRIP1/FANCJ Homologue and Functions in Interstrand Cross-Link Repair Mol. Cell. Biol., March 1, 2008; 28(5): 1470 - 1479. [Abstract] [Full Text] [PDF]
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 N. Spardy, A. Duensing, D. Charles, N. Haines, T. Nakahara, P. F. Lambert, and S. Duensing The Human Papillomavirus Type 16 E7 Oncoprotein Activates the Fanconi Anemia (FA) Pathway and Causes Accelerated Chromosomal Instability in FA Cells J. Virol., December 1, 2007; 81(23): 13265 - 13270. [Abstract] [Full Text] [PDF]
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 Y. Nomura, N. Adachi, and H. Koyama Human Mus81 and FANCB independently contribute to repair of DNA damage during replication Genes Cells, October 1, 2007; 12(10): 1111 - 1122. [Abstract] [Full Text] [PDF]
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 C. Jacquemont and T. Taniguchi Proteasome Function Is Required for DNA Damage Response and Fanconi Anemia Pathway Activation Cancer Res., August 1, 2007; 67(15): 7395 - 7405. [Abstract] [Full Text] [PDF]
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J. M. Hinz, P. B. Nham, S. S. Urbin, I. M. Jones, and L. H. Thompson Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis Nucleic Acids Res., June 28, 2007; 35(11): 3733 - 3740. [Abstract] [Full Text] [PDF]
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A. Sobeck, S. Stone, and M. E. Hoatlin DNA Structure-Induced Recruitment and Activation of the Fanconi Anemia Pathway Protein FANCD2 Mol. Cell. Biol., June 15, 2007; 27(12): 4283 - 4292. [Abstract] [Full Text] [PDF]
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X. Wang, R. D. Kennedy, K. Ray, P. Stuckert, T. Ellenberger, and A. D. D'Andrea Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway Mol. Cell. Biol., April 15, 2007; 27(8): 3098 - 3108. [Abstract] [Full Text] [PDF]
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R. K. Nookala, S. Hussain, and L. Pellegrini Insights into Fanconi Anaemia from the structure of human FANCE Nucleic Acids Res., March 12, 2007; 35(5): 1638 - 1648. [Abstract] [Full Text] [PDF]
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E. Gallmeier, T. Hucl, J. R. Brody, D. A. Dezentje, K. Tahir, J. Kasparkova, V. Brabec, K. E. Bachman, and S. E. Kern High-Throughput Screening Identifies Novel Agents Eliciting Hypersensitivity in Fanconi Pathway-Deficient Cancer Cells Cancer Res., March 1, 2007; 67(5): 2169 - 2177. [Abstract] [Full Text] [PDF]
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S. Seki, M. Ohzeki, A. Uchida, S. Hirano, N. Matsushita, H. Kitao, T. Oda, T. Yamashita, N. Kashihara, A. Tsubahara, et al. A requirement of FancL and FancD2 monoubiquitination in DNA repair Genes Cells, March 1, 2007; 12(3): 299 - 310. [Abstract] [Full Text] [PDF]
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 P. Kowal, A. M. Gurtan, P. Stuckert, A. D. D'Andrea, and T. Ellenberger Structural Determinants of Human FANCF Protein That Function in the Assembly of a DNA Damage Signaling Complex J. Biol. Chem., January 19, 2007; 282(3): 2047 - 2055. [Abstract] [Full Text] [PDF]
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 F. Weber, Y. Xu, L. Zhang, A. Patocs, L. Shen, P. Platzer, and C. Eng Microenvironmental Genomic Alterations and Clinicopathological Behavior in Head and Neck Squamous Cell Carcinoma JAMA, January 10, 2007; 297(2): 187 - 195. [Abstract] [Full Text] [PDF]
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 E. Gallmeier and S. E. Kern Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models Clin. Cancer Res., January 1, 2007; 13(1): 4 - 10. [Abstract] [Full Text] [PDF]
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 Y. Wang and H. G. Dohlman Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination: Insights From Model Organisms Circ. Res., December 8, 2006; 99(12): 1305 - 1314. [Abstract] [Full Text] [PDF]
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J. Dunn, M. Potter, A. Rees, and T. M. Runger Activation of the Fanconi Anemia/BRCA Pathway and Recombination Repair in the Cellular Response to Solar Ultraviolet Light Cancer Res., December 1, 2006; 66(23): 11140 - 11147. [Abstract] [Full Text] [PDF]
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 Y. Wang, T. Wiltshire, J. Senft, S. L. Wenger, E. Reed, and W. Wang Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven Mol. Cancer Ther., December 1, 2006; 5(12): 3153 - 3161. [Abstract] [Full Text] [PDF]
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T. Pejovic, J. E. Yates, H. Y. Liu, L. E. Hays, Y. Akkari, Y. Torimaru, W. Keeble, R. K. Rathbun, W. H. Rodgers, A. E. Bale, et al. Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. Cancer Res., September 15, 2006; 66(18): 9017 - 9025. [Abstract] [Full Text] [PDF]
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A. L. Medhurst, E. H. Laghmani, J. Steltenpool, M. Ferrer, C. Fontaine, J. de Groot, M. A. Rooimans, R. J. Scheper, A. R. Meetei, W. Wang, et al. Evidence for subcomplexes in the Fanconi anemia pathway Blood, September 15, 2006; 108(6): 2072 - 2080. [Abstract] [Full Text] [PDF]
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G. P. H. Ho, S. Margossian, T. Taniguchi, and A. D. D'Andrea Phosphorylation of FANCD2 on Two Novel Sites Is Required for Mitomycin C Resistance. Mol. Cell. Biol., September 1, 2006; 26(18): 7005 - 7015. [Abstract] [Full Text] [PDF]
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 E. Barroso, R.L. Milne, L.P. Fernandez, P. Zamora, J.I. Arias, J. Benitez, and G. Ribas FANCD2 associated with sporadic breast cancer risk Carcinogenesis, September 1, 2006; 27(9): 1930 - 1937. [Abstract] [Full Text] [PDF]
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N. McCabe, N. C. Turner, C. J. Lord, K. Kluzek, A. Bialkowska, S. Swift, S. Giavara, M. J. O'Connor, A. N. Tutt, M. Z. Zdzienicka, et al. Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition Cancer Res., August 15, 2006; 66(16): 8109 - 8115. [Abstract] [Full Text] [PDF]
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 R. D. Kennedy and A. D. D'Andrea DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes J. Clin. Oncol., August 10, 2006; 24(23): 3799 - 3808. [Abstract] [Full Text] [PDF]
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H. Kitao, K. Yamamoto, N. Matsushita, M. Ohzeki, M. Ishiai, and M. Takata Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair J. Biol. Chem., July 28, 2006; 281(30): 21312 - 21320. [Abstract] [Full Text] [PDF]
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X. Yu, S. Fu, M. Lai, R. Baer, and J. Chen BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes & Dev., July 1, 2006; 20(13): 1721 - 1726. [Abstract] [Full Text] [PDF]
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W. Zhu and A. Dutta An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G2/M Checkpoint and DNA Damage Repair upon Rereplication Mol. Cell. Biol., June 15, 2006; 26(12): 4601 - 4611. [Abstract] [Full Text] [PDF]
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T. Taniguchi and A. D. D'Andrea Molecular pathogenesis of Fanconi anemia: recent progress Blood, June 1, 2006; 107(11): 4223 - 4233. [Abstract] [Full Text] [PDF]
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D. Chirnomas, T. Taniguchi, M. de la Vega, A. P. Vaidya, M. Vasserman, A.-R. Hartman, R. Kennedy, R. Foster, J. Mahoney, M. V. Seiden, et al. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol. Cancer Ther., April 1, 2006; 5(4): 952 - 961. [Abstract] [Full Text] [PDF]
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A. Sobeck, S. Stone, V. Costanzo, B. de Graaf, T. Reuter, J. de Winter, M. Wallisch, Y. Akkari, S. Olson, W. Wang, et al. Fanconi Anemia Proteins Are Required To Prevent Accumulation of Replication-Associated DNA Double-Strand Breaks Mol. Cell. Biol., January 15, 2006; 26(2): 425 - 437. [Abstract] [Full Text] [PDF]
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R. D. Kennedy and A. D. D'Andrea The Fanconi Anemia/BRCA pathway: new faces in the crowd Genes & Dev., December 15, 2005; 19(24): 2925 - 2940. [Abstract] [Full Text] [PDF]
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 S. Houghtaling, A. Newell, Y. Akkari, T. Taniguchi, S. Olson, and M. Grompe Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining Hum. Mol. Genet., October 15, 2005; 14(20): 3027 - 3033. [Abstract] [Full Text] [PDF]
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 J. Zhang and S. N. Powell The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair Mol. Cancer Res., October 1, 2005; 3(10): 531 - 539. [Abstract] [Full Text] [PDF]
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Y.-G. Yang, Z. Herceg, K. Nakanishi, I. Demuth, C. Piccoli, J. Michelon, G. Hildebrand, M. Jasin, M. Digweed, and Z.-Q. Wang The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells Carcinogenesis, October 1, 2005; 26(10): 1731 - 1740. [Abstract] [Full Text] [PDF]
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K. M. Austin, R. J. Leary, and A. Shimamura The Shwachman-Diamond SBDS protein localizes to the nucleolus Blood, August 15, 2005; 106(4): 1253 - 1258. [Abstract] [Full Text] [PDF]
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Q. Chen, P. C. Van der Sluis, D. Boulware, L. A. Hazlehurst, and W. S. Dalton The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells Blood, July 15, 2005; 106(2): 698 - 705. [Abstract] [Full Text] [PDF]
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W.-H. Park, S. Margossian, A. A. Horwitz, A. M. Simons, A. D. D'Andrea, and J. D. Parvin Direct DNA Binding Activity of the Fanconi Anemia D2 Protein J. Biol. Chem., June 24, 2005; 280(25): 23593 - 23598. [Abstract] [Full Text] [PDF]
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S. Eladad, T.-Z. Ye, P. Hu, M. Leversha, S. Beresten, M. J. Matunis, and N. A. Ellis Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification Hum. Mol. Genet., May 15, 2005; 14(10): 1351 - 1365. [Abstract] [Full Text] [PDF]
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N. G. Howlett, T. Taniguchi, S. G. Durkin, A. D. D'Andrea, and T. W. Glover The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability Hum. Mol. Genet., March 1, 2005; 14(5): 693 - 701. [Abstract] [Full Text] [PDF]
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R. Montes de Oca, P. R. Andreassen, S. P. Margossian, R. C. Gregory, T. Taniguchi, X. Wang, S. Houghtaling, M. Grompe, and A. D. D'Andrea Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin Blood, February 1, 2005; 105(3): 1003 - 1009. [Abstract] [Full Text] [PDF]
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J. Mi and G. M. Kupfer The Fanconi anemia core complex associates with chromatin during S phase Blood, January 15, 2005; 105(2): 759 - 766. [Abstract] [Full Text] [PDF]
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K. Yamamoto, S. Hirano, M. Ishiai, K. Morishima, H. Kitao, K. Namikoshi, M. Kimura, N. Matsushita, H. Arakawa, J.-M. Buerstedde, et al. Fanconi Anemia Protein FANCD2 Promotes Immunoglobulin Gene Conversion and DNA Repair through a Mechanism Related to Homologous Recombination Mol. Cell. Biol., January 1, 2005; 25(1): 34 - 43. [Abstract] [Full Text] [PDF]
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S. Houghtaling, L. Granville, Y. Akkari, Y. Torimaru, S. Olson, M. Finegold, and M. Grompe Heterozygosity for p53 (Trp53+/-) Accelerates Epithelial Tumor Formation in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice Cancer Res., January 1, 2005; 65(1): 85 - 91. [Abstract] [Full Text] [PDF]
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B. W. Freie, S. L. M. Ciccone, X. Li, P. A. Plett, C. M. Orschell, E. F. Srour, H. Hanenberg, D. Schindler, S.-H. Lee, and D. W. Clapp A Role for the Fanconi Anemia C Protein in Maintaining the DNA Damage-induced G2 Checkpoint J. Biol. Chem., December 3, 2004; 279(49): 50986 - 50993. [Abstract] [Full Text] [PDF]
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J. Mi, F. Qiao, J. B. Wilson, A. A. High, M. J. Schroeder, P. T. Stukenberg, A. Moss, J. Shabanowitz, D. F. Hunt, N. J. Jones, et al. FANCG Is Phosphorylated at Serines 383 and 387 during Mitosis Mol. Cell. Biol., October 1, 2004; 24(19): 8576 - 8585. [Abstract] [Full Text] [PDF]
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F. Leveille, E. Blom, A. L. Medhurst, P. Bier, E. H. Laghmani, M. Johnson, M. A. Rooimans, A. Sobeck, Q. Waisfisz, F. Arwert, et al. The Fanconi Anemia Gene Product FANCF Is a Flexible Adaptor Protein J. Biol. Chem., September 17, 2004; 279(38): 39421 - 39430. [Abstract] [Full Text] [PDF]
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P. R. Andreassen, A. D. D'Andrea, and T. Taniguchi ATR couples FANCD2 monoubiquitination to the DNA-damage response Genes & Dev., August 15, 2004; 18(16): 1958 - 1963. [Abstract] [Full Text] [PDF]
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X. Wang, P. R. Andreassen, and A. D. D'Andrea Functional Interaction of Monoubiquitinated FANCD2 and BRCA2/FANCD1 in Chromatin Mol. Cell. Biol., July 1, 2004; 24(13): 5850 - 5862. [Abstract] [Full Text] [PDF]
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S. Hussain, J. B. Wilson, A. L. Medhurst, J. Hejna, E. Witt, S. Ananth, A. Davies, J.-Y. Masson, R. Moses, S. C. West, et al. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways Hum. Mol. Genet., June 15, 2004; 13(12): 1241 - 1248. [Abstract] [Full Text] [PDF]
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A. Rothfuss and M. Grompe Repair Kinetics of Genomic Interstrand DNA Cross-Links: Evidence for DNA Double-Strand Break-Dependent Activation of the Fanconi Anemia/BRCA Pathway Mol. Cell. Biol., January 1, 2004; 24(1): 123 - 134. [Abstract] [Full Text] [PDF]
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 S. Polo, S. Confalonieri, A. E. Salcini, and P. P. Di Fiore EH and UIM: Endocytosis and More Sci. Signal., December 16, 2003; 2003(213): re17 - re17. [Abstract] [Full Text] [PDF]
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S. Hussain, E. Witt, P. A.J. Huber, A. L. Medhurst, A. Ashworth, and C. G. Mathew Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1 Hum. Mol. Genet., October 1, 2003; 12(19): 2503 - 2510. [Abstract] [Full Text] [PDF]
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J. C.Y. Wong, N. Alon, C. Mckerlie, J. R. Huang, M. S. Meyn, and M. Buchwald Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia Hum. Mol. Genet., August 15, 2003; 12(16): 2063 - 2076. [Abstract] [Full Text] [PDF]
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S. Houghtaling, C. Timmers, M. Noll, M. J. Finegold, S. N. Jones, M. S. Meyn, and M. Grompe Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice Genes & Dev., August 15, 2003; 17(16): 2021 - 2035. [Abstract] [Full Text] [PDF]
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A. D. D'Andrea The Fanconi road to cancer Genes & Dev., August 15, 2003; 17(16): 1933 - 1936. [Full Text] [PDF]
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S. L. Donahue, R. Lundberg, R. Saplis, and C. Campbell Deficient Regulation of DNA Double-strand Break Repair in Fanconi Anemia Fibroblasts J. Biol. Chem., August 8, 2003; 278(32): 29487 - 29495. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
FANCA, FANCC, FANCD2,
FANCE, FANCF, and FANCG
