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 CCAR1 loss abrogated FANCA protein without substantial reduction in the level

10 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-

11 monly involving BRCA1, ARID1A, ATM, ATR, and FANCA.

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

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

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

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

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

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

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

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

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

21 ct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRK

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

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

24 hibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received o

25 EN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2.

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

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

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

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

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

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

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

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

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

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

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

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

38 1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity.

39 POLG, Fanconi anaemia genes include FANCD2, FANCA, FANCG, ERCC4, FANCE and FANCI, while DNA mismatch

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

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

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

43 ates with FANCA pre-mRNA and is required for FANCA mRNA processing.

44 e in the FA/BRCA pathway and is required for FANCA protein expression in human cells.

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

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

47 Inactivation of the Fanconi anemia gene FANCA; the human silencing hub (HUSH)-associated methylt

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

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

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

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

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

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

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

55 y on a mutation in one of the 22 FANC genes (FANCA-W) involved in a common interstrand DNA crosslink-

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

57 QTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes

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

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

60 CCAR1 prevents inclusion of a poison exon in FANCA.

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

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

63 Mutations in FANCA account for more than 60% of FA cases worldwide(3,

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

65 t in DNA repair due to germline mutations in FANCA, FANCB, FANCC, FANCI or BRIP1/FANCJ or proficient

66 EUFA867 also carries biallelic mutations in FANCA.

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

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

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

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

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

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

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

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

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

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

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

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

79 The observed FANCA-mediated suppression of hyperplasia correlated wit

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

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

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

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

84 tion, and proteasome-mediated degradation of FANCA.

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

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

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

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

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

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

91 man and mouse cells that loss-of-function of FANCA or FANCC, products of 2 genes affecting more than

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

93 ally, we demonstrated that the inhibition of FANCA, SETDB1, or MORC3 also enhanced transgene expressi

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

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

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

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

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

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

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

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

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

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

104 ordance between the localization patterns of FANCA and FANCG.

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

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

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

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

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

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

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

112 O5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epist

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

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

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

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

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

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

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

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

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

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

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

124 direct interaction with the FA gene product, FANCA.

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

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

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

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

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

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

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

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

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

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

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

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

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

138 FANCA transcript, thereby leading to reduced FANCA protein expression.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

153 The FANCA haplotype that included G501S also conferred incre

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

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

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

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

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

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

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

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

162 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA prote

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

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

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

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

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

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

169 odulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular

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

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

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

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

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

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

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

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

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

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

180 es of BMF were transduced with a therapeutic FANCA-encoding lentiviral vector and re-infused without

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

182 s and assessed as not related to therapeutic FANCA-encoding lentiviral vector.

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

184 licing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in al

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

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

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

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

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

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

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

192 erestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing

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

194 tail on DNA facilitates its interaction with FANCA.