ライフサイエンスコーパス: FANCA

1 FANCA also binds to RNA with an intriguingly higher affi

2 FANCA and FANCG are dispensable for maximal in vitro ubi

3 FANCA binds to both single-stranded (ssDNA) and double-s

4 FANCA is phosphorylated after DNA damage and localized t

5 FANCA requires a certain length of nucleic acids for opt

6 FANCA, FANCC, FANCG, and FANCF proteins form a multisubu

7 The Fanconi anemia complementation group A (FANCA) gene is one of 15 disease-causing genes and has b

8 and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-kappaB/AP-

9 adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-

10 s for core complex member proteins FANCG and FANCA by phosphorylation.

11 Moreover, at least one function of FANCG and FANCA is to regulate the nuclear accumulation of the FA

12 of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as

13 ation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8).

14 By testing the affinity between FANCA and a variety of DNA structures, we found that a 5

15 ivo but also induces the interaction between FANCA and FANCG.

16 Both FANCA and FANCG proteins exist as monomers under non-oxi

17 rexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or FANC

18 and a weaker interaction of FANCE with both FANCA and FANCG.

19 dation and also allows their coregulation by FANCA and FANCM during nuclear localization.

20 tiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may co

21 Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in

22 deficient for the FA core complex component FANCA but could be restored in corrected cells.

23 port here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in h

24 nent of a nuclear protein complex containing FANCA and FANCC.

25 On the contrary, FANCA exhibits a two-phase incision regulation when DNA

26 Moreover, cytoplasmic FANCA and FANCC formed a cytoplasmic complex and interac

27 The molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal.

28 FANCC, we demonstrated that the cytoplasmic FANCA-FANCC complex was essential for NPMc stability.

29 In response to DNA damage, FANCA-deficient patient-derived keratinocyte cultures di

30 A patient-derived FANCA truncation mutant (Q772X) has diminished affinity

31 Importantly, the knockdown of either FANCA or FANCD2 in HPV-positive keratinocytes was suffic

32 lelic germline mutations in all 27 families: FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3),

33 1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity.

34 t study the functional consequences of FANCG/FANCA binding were examined.

35 We used affinity pulldown of FLAG-FANCA to pull down the FA complex from whole-cell extrac

36 Similar immunolocalization for FANCA and FANCG suggested that these proteins interact i

37 e minimum number of nucleotides required for FANCA recognition is approximately 30 for both DNA and R

38 esting that regulated release of FAAP20 from FANCA is a critical step in the normal FA pathway.

39 c hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the secon

40 Fanconi anemia complementation group A gene (FANCA) (G501S) was associated with increased risk of CIN

41 by defects in at least eight distinct genes FANCA, B, C, D1, D2, E, F and G.

42 Mutations in 16 genes (FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, and Q

43 A repair pathway including at least 6 genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG).

44 nes orthologous to all nine cloned FA genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG

45 tions in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized

46 with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cyto

47 ome with at least 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG

48 Using purified protein, we report that human FANCA has intrinsic affinity for nucleic acids.

49 FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism.

50 d a patient with FA with a point mutation in FANCA, which encodes a mutant FANCA protein (FANCAI939S)

51 nd patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outco

52 EUFA867 also carries biallelic mutations in FANCA.

53 e FANCG complementary DNA (cDNA) resulted in FANCA/FANCG binding, prolongation of the cellular half-l

54 dditional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are requi

55 usly reported FA-binding proteins, including FANCA, FANCC, FANCG, cdc2, and GRP94, thus validating th

56 -iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines.

57 ation and characterization of a novel 20-kDa FANCA-associated protein (FAAP20).

58 equires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and no

59 hroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of col

60 nt mutation in FANCA, which encodes a mutant FANCA protein (FANCAI939S).

61 Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severe

62 xpression and reduced function of the mutant FANCA (R880Q) protein.

63 cells deficient for BRCA1 or FANCD2, but not FANCA.

64 ) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L.

65 The observed FANCA-mediated suppression of hyperplasia correlated wit

66 ns of these proteins to amino acids 18-29 of FANCA and to two noncontiguous carboxyl-terminal domains

67 op, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overprodu

68 ition to the previously described binding of FANCA to FANCG, we now demonstrate direct interaction of

69 not only triggers the multimeric complex of FANCA and FANCG in vivo but also induces the interaction

70 tion, and proteasome-mediated degradation of FANCA.

71 Finally, depletion of FANCA and FANCC in NPMc-positive leukemic cells signific

72 ting that the nucleic acid-binding domain of FANCA is located primarily at its C terminus, where most

73 All exons of FANCA and FANCG were sequenced, and no mutations were fo

74 Conversely, stable expression of FANCA mutants encoding intact FANCG interaction domains

75 Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutat

76 PMc but also suggest cytoplasmic function of FANCA and FANCC in NPMc-related leukemogenesis.

77 The complementation function of FANCA was abolished by mutations in its FANCG-binding do

78 abolishes multimerization and interaction of FANCA and FANCG in vitro.

79 We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hemato

80 Knockdown of FANCA or FANCC in leukemic OCI/AML3 cells induced rapid

81 g, prolongation of the cellular half-life of FANCA, and an increase in the nuclear accumulation of th

82 for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway.

83 ng activity or intracellular localization of FANCA may promote cytogenetic instability and clonal pro

84 llow-up experiments established that loss of FANCA function was associated with platinum hypersensiti

85 Site-directed mutagenesis of FANCA residues 18-29 revealed a novel arginine-rich inte

86 minal nuclear localization sequence (NLS) of FANCA, suggesting that FANCG plays a role in regulating

87 Overexpression of FANCA restored levels of both FANCA and FANCG, whereas o

88 ordance between the localization patterns of FANCA and FANCG.

89 Phosphorylation of FANCA on serine 1449 is a DNA damage-specific event that

90 The amino terminal portion of FANCA and the central part (aa 740-1083) of BRCA1 contai

91 here the growth and molecular properties of FANCA-deficient versus FANCA-corrected HPV E6/E7 immorta

92 tation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells.

93 require replication but support the role of FANCA variants in cervical cancer susceptibility and of

94 Mutation of the SUMOylation site of FANCA rescued the expression of the mutant protein.

95 Mass spectrometry of FANCA revealed one phosphopeptide, phosphorylated on ser

96 Moreover, targeting of FANCA to the nucleus or the cytoplasm with nuclear local

97 Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, F

98 Fluorescent-tagged versions of FANCA, FANCC, and FANCG colocalize in cytoplasm and nucl

99 We identify a region on FANCA that physically interacts with FAAP20, and show th

100 FAAP20 binding exposed a SUMOylation site on FANCA at amino acid residue K921, resulting in E2 SUMO-c

101 f a G2-phase arrest even when ATR, BRCA1, or FANCA is absent.

102 ated DNA, because the loss of ATR, BRCA1, or FANCA promotes apoptosis and suppresses the accumulation

103 Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomere

104 a different haplotype that included 2 other FANCA SNPs (G809A and T266A).

105 is dependent on ATR, and ATR phosphorylated FANCA on serine 1449 in vitro.

106 nd to chromatin that contains phosphorylated FANCA after undergoing DNA damage.

107 direct interaction with the FA gene product, FANCA.

108 CC and of the other cloned FA gene products (FANCA and FANCG) remain unknown.

109 the 11 cloned Fanconi anemia gene products (FANCA, -B, -C, -E, -F, -G, -L, and -M) form a multisubun

110 The 6 known Fanconi anemia gene products (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG proteins)

111 coni anemia complementation group A protein (FANCA), greatly enhances MUS81-EME1-mediated ICL incisio

112 s the nuclear accumulation of FANCC protein, FANCA-FANCC complex formation, monoubiquitination and nu

113 s a complex with the Fanconi anemia proteins FANCA, FANCC, and FANCG.

114 The FA proteins FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL participate

115 Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form

116 At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear core comp

117 Five of the FA proteins (FANCA, C, E, F and G) interact in a nuclear complex upst

118 ned, and at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubuni

119 and at least three of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a nuclear com

120 a BM extract to show that three FA proteins, FANCA, FANCC, and FANCG, functionally interact with the

121 esting that FANCG plays a role in regulating FANCA nuclear accumulation.

122 expression of FANCG or FANCC did not restore FANCA levels.

123 that binding of FANCG to the amino terminal FANCA NLS sequence is necessary but not sufficient for t

124 gether, our results lead us to conclude that FANCA and FANCG uniquely respond to oxidative damage by

125 These results demonstrate that FANCA-FANCG complexes are required for cellular resistan

126 US81-EME1 on ICL damage and establishes that FANCA regulates the incision activity of MUS81-EME1 in a

127 Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear

128 soralen ICL formation in cells, we find that FANCA interacts with and recruits MUS81 to ICL lesions.

129 Given that FANCA, FANCC, and FANCG complementation groups account f

130 Protein interaction studies indicated that FANCA and FANCG bind directly to mu-calpain.

131 Here we show that FANCA and FANCG are redox-sensitive proteins that are mu

132 sically interacts with FAAP20, and show that FANCA regulates stability of this protein.

133 The FANCA and FANCG proteins deficient in FA groups A and G

134 The FANCA gene appears to play a role in the stability or ex

135 The FANCA haplotype that included G501S also conferred incre

136 On the basis of 2-hybrid analysis, the FANCA/FANCG binding is a direct protein-protein interact

137 between BRCA2 or its effector RAD51 and the FANCA, FANCC and FANCG proteins.

138 the cytoplasm, we suggest that FANCC and the FANCA-FANCG complexes suppress MMC cytotoxicity within d

139 ence for direct interaction only between the FANCA protein and BRCA1.

140 e show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for

141 After correcting the FANCA defect in EUFA867 lymphoblasts, a "clean" FA-M cel

142 A variant in the FANCA gene (rs1061646, 0.15-0.68 frequency across popula

143 d to be somatic mosaics for mutations in the FANCA gene.

144 In primary human BM cells, mutations in the FANCA, FANCC, and FANCG genes markedly increase the amou

145 o and stabilized the endogenous forms of the FANCA and FANCC proteins in the FA-G cells.

146 XRCC9 protein is required for binding of the FANCA and FANCC proteins.

147 been demonstrated by the interaction of the FANCA and FANCD2 proteins with BRCA1, and the discovery

148 In the current study, mutant forms of the FANCA and FANCG proteins have been generated and analyze

149 These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed

150 The amino-terminal region of the FANCA protein is required for FANCG binding, FANCC bindi

151 nal nuclear localization signal (NLS) of the FANCA protein.

152 n of HR, which is minimally dependent on the FANCA, FANCC, and FANCG proteins, does not require FANCD

153 DNA damage and during S-phase, requiring the FANCA, C, E and G proteins to do so.

154 We have previously demonstrated that the FANCA and FANCC proteins interact and form a nuclear com

155 soralen interstrand cross-links and that the FANCA, FANCC, and FANCG proteins are bound to this damag

156 These results demonstrate that the FANCA/FANCG interaction is required to maintain the cell

157 gma* forms a complex in the nucleus with the FANCA and FANCC proteins.

158 mal clone was exclusive to colonies with the FANCA exon 29 mutation.

159 ve been identified so far, and five of them (FANCA, -C, -E, -F, and -G) assemble in a multinuclear co

160 cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vit

161 eraction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting.

162 Studies using truncated FANCA proteins indicate that both the N- and C-moieties

163 Wild-type FANCA was also subject to SUMOylation, RNF4-mediated pol

164 We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway comp

165 lecular properties of FANCA-deficient versus FANCA-corrected HPV E6/E7 immortalized keratinocytes in

166 ast two-hybrid analysis to determine whether FANCA, FANCC, FANCF, and FANCG directly interact with ER

167 gged FANCE protein coimmunoprecipitates with FANCA, FANCC, and FANCG but not with FANCD2.

168 he carboxy terminus, binds in a complex with FANCA and translocates to the nucleus; however, this mut

169 domain is not required for interaction with FANCA, but is required for DNA-damage-induced chromatin

170 tail on DNA facilitates its interaction with FANCA.