ライフサイエンスコーパス: FANCD2

1 or recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2).

2 molecule is conjugated to each of FANCI and FANCD2.

3 lament formation in cells lacking functional FANCD2.

4 , is recruited to ICLs by ubiquitinated (Ub) Fancd2.

5 way that does not require incisions or FANCI-FANCD2.

6 ation because of downregulation of RAD51 and FANCD2.

7 ysical and functional interaction partner of FANCD2.

8 U, except for cells absent for expression of FANCD2.

9 he Fanconi anemia core complex but not FancI-FancD2.

10 ntify CtIP as a novel interaction partner of FANCD2.

11 vating this pathway is monoubiquitination of FANCD2.

12 y of the complex and by directly recognizing FANCD2.

13 ion of ATM, accompanied with the decrease of FANCD2.

14 e effect of EGFR mutation was epistatic with FANCD2.

15 ATM-Chk2 checkpoint activation by sustaining FANCD2.

16 h was rescued by reintroduction of wild-type FANCD2.

17 l monoubiquitylation-independent function of FANCD2.

18 nit (LSU) pre-rRNA processing independent of FANCD2.

19 AD51 and stimulated D-loop formation, unlike FANCD2.

20 CHK1 and RPA, and the mono-ubiquitination of FANCD2.

21 n cells that carry the non-monoubiquitinated FANCD2.

22 FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3), FANCF (2), FANCG (2), FANCI (1), FANCJ (2),

23 The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein.

24 on of the FAAP20 acetylation pathway impairs FANCD2 activation.

25 uitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to res

26 FANCD2 acts independently of previous S phases to promot

27 FANCD2 also functions during the replication stress resp

28 The double knockout Fanci-/- Fancd2-/- also showed epistatic relationship for hematol

29 During replication stress, FANCD2 and BLM cooperate to promote restart of stalled r

30 ncreatic cancers abolishes recruitment by Ub-Fancd2 and causes genetic instability without affecting

31 CA1 reduced binding to co-factors, PALB2 and FANCD2 and decreased phosphorylation of p53.

32 How FANCD2 and FANCI are anchored to chromatin remains unkno

33 In chromatin, both FANCD2 and FANCI associate with SF3B1, prevent accumulat

34 R) kinase, followed by monoubiquitination of FANCD2 and FANCI by the FA core complex.

35 ermine the structures of recombinant chicken FANCD2 and FANCI complexes.

36 We propose that FANCD2 and FANCI contribute to the organization of funct

37 FANCD2 and FANCI function together in the Fanconi anemia

38 implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulato

39 FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs within chromatin

40 gase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined.

41 pillar cells require Fanconi anemia proteins FANCD2 and FANCI, as well as Blm helicase, but not canon

42 mediates recruitment of two central players, FANCD2 and FANCI, to sites of stalled replication forks.

43 Ubiquitin is positioned at the interface of FANCD2 and FANCI, where it acts as a covalent molecular

44 plex, which monoubiquitinates its substrates FANCD2 and FANCI.

45 We demonstrate the interaction of FANCD2 and FANCJ in vivo and in vitro by immunoprecipita

46 controls the step-wise recruitment of MRE11, FANCD2 and finally CtIP to stalled replication forks, fo

47 out models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher

48 Deletion of both Fancd2 and Foxo3a led to an initial expansion followed b

49 mplex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink re

50 n of FA pathway is the monoubiquitination of FANCD2 and its binding partner FANCI.

51 Intriguingly, FANCD2 and its interaction partners are also involved in

52 of XPF-ERCC1 and SLX4 to the ICL depends on FANCD2 and its ubiquitylation.

53 RX forms a constitutive protein complex with FANCD2 and protects FANCD2 from proteasomal degradation.

54 ir of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi

55 Our data suggest that FANCD2 and RAD51 have an important role in PCNA monoubiq

56 Here we show that the Fanconi anemia protein Fancd2 and stress transcriptional factor Foxo3a cooperat

57 Fancd2 (-/-) and wildtype (WT) mice were fed a standard

58 results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality.

59 inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci.

60 portant for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway

61 as rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unh

62 signal on chromosome 15, likely underlain by FANCD2- and FANCI-associated nuclease 1 (FAN1), a nuclea

63 nt mechanisms, we generated isogenic FANCI-, FANCD2- and FANCI:FANCD2 double-null cells.

64 In addition, FANCD2, another Fanconi Anemia (FA) protein, is also req

65 hat gammaH2AX and monoubiquitinated PCNA and FANCD2 are constitutively up-regulated in oxaliplatin-re

66 with this suggestion we found that REV1 and FANCD2 are epistatic with respect to sensitivity to the

67 We show that FANCI and FANCD2 are partially independent regarding their protein

68 conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warrant

69 telangiectasia mutated (ATM), MDC1, WRN, and FANCD2 are specifically recruited to TIPs but not to non

70 ctively, these findings provide evidence for Fancd2 as a crucial regulator of mitochondrion biosynthe

71 Here, we identify and describe a role for FANCD2 as a trans-acting facilitator of CFS replication,

72 Here we show that FANCI and FANCD2 associate with splicing factor 3B1 (SF3B1), a key

73 icated CFS regions in mitosis, detectable as FANCD2-associated chromosomal sites that were transmitte

74 Although FANCD2-associated nuclease 1 (FAN1) contributes to ICL r

75 Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-s

76 re we investigated how the 5' flap nucleases FANCD2-associated nuclease 1 (FAN1), exonuclease 1 (EXO1

77 We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and

78 put mass spectrometry approach to search for Fancd2-binding proteins in different mouse organs.

79 Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD afte

80 epends on BRCA1 and BRCA2, components of the FANCD2/BRCA supercomplex.

81 e FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy.

82 sensitivity in cells deficient for BRCA1 or FANCD2, but not FANCA.

83 Simultaneously, FANCD2-but not FANCI-plays a major role in HDR-mediated

84 in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL.

85 tination of Fanconi anemia group D2 protein (FANCD2) by the multisubunit ubiquitin E3 ligase, the FA

86 Similarly, non-ubiquitinated FANCD2 can still support proliferation cell nuclear anti

87 o what was observed in non-monoubiquitinated FANCD2-carrying cells.

88 Disruption of the HBD/MBD compromises FANCD2 chromatin binding and nuclear focus formation and

89 FANCJ is necessary for FANCD2 chromatin loading and focus formation in response

90 iRNA silencing of DNA repair genes, BRCA2 or FANCD2, compared to control cells.

91 spontaneous SCE formation relative to their FANCD2-complemented counterparts, suggesting that this o

92 tion of Foxo3a in HSCs, and re-expression of Fancd2 completely restored nuclear Foxo3a localization.

93 FAN1 joins the BLM-FANCD2 complex following APH-mediated fork stalling in a

94 r results reveal how monoubiquitinated FANCI:FANCD2, defective in many cancer types and all cases of

95 Furthermore, FANCD2 deficiency is associated with DNA:RNA hybrid form

96 Fancd2 deficiency strongly promoted cytoplasmic localiza

97 PolH chromatin localization is decreased in FANCD2 deficient cells, FANCD2 siRNA knockdown cells and

98 Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabi

99 press endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-

100 Similarly, FANCD2-deficient fibroblasts (PD20) derived from Fanconi

101 In FANCD2-deficient lymphoblasts, FANCD2 is essential to su

102 Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven s

103 one H3 chaperone activities of ATRX/DAXX and FANCD2, demonstrating that coordinated histone H3 varian

104 In contrast, FANCI is dispensable for FANCD2-dependent BLMcx regulation, demonstrating functio

105 age is prevented, unhooking occurs via FANCI-FANCD2-dependent incisions.

106 o address if FANCI is also involved in these FANCD2-dependent mechanisms, we generated isogenic FANCI

107 ks collide with the lesion, leading to FANCI-FANCD2-dependent unhooking and formation of a double-str

108 n of the FA pathway does not trigger ALT, as FANCD2 depleted telomerase positive cells do not acquire

109 systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is depe

110 RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system.

111 tance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting.

112 CD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the respons

113 tivity is redundant with that of RAD51AP1 in FANCD2 deubiquitination, it is required for efficient HR

114 eover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, bu

115 generated isogenic FANCI-, FANCD2- and FANCI:FANCD2 double-null cells.

116 s common and distinct functions of FANCI and FANCD2 during mouse development, meiotic recombination a

117 xp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression.

118 Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulato

119 Here we demonstrate that FANCD2 expression is reduced in UM and that ectopic expr

120 D2(Ub) isoform is dispensable for functional FANCD2-FAN1 cross talk during stalled fork recovery.

121 interacts selectively with monoubiquitinated FANCD2 (FANCD2(Ub)) at ICLs.

122 g motifs, on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1.

123 uitination of FA effector proteins FANCI and FANCD2 (FANCI-D2) and required the viral DNA polymerase.

124 FANCD2-FANCI adopts a closed conformation when the FANCD

125 our results uncover the mechanism of how the FANCD2-FANCI complex activates the FA pathway, and expla

126 the first structural insight into the human FANCD2-FANCI complex by obtaining the cryo-EM structure.

127 We show that the FANCD2-FANCI complex forms independently of ATR and FA c

128 The FANCD2-FANCI complex is central to the pathway, and loca

129 for mediating the monoubiquitination of the FANCD2-FANCI complex.

130 rosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases

131 Together, our work suggests that FANCD2-FANCI is a clamp that is locked onto DNA by ubiqu

132 tination of a pseudosymmetric heterodimer of FANCD2-FANCI(4,5) by the FA core complex-a megadalton mu

133 hat recessive mutations in the gene encoding FANCD2/FANCI-associated nuclease 1 (FAN1) cause KIN in h

134 Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans lead

135 ors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which en

136 ptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form.

137 Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a p

138 ic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for che

139 Surprisingly, depleting BRCA1 or FANCD2 (Fanconi anemia [FA] proteins) or BRG1, a mSWI/SN

140 stalling in a manner dependent on MRE11 and FANCD2, followed by FAN1 nuclease-mediated fork restart.

141 ing Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing

142 oscopy that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA.

143 tion, demonstrating functional separation of FANCD2 from FANCI.

144 pathway activation triggers dissociation of FANCD2 from FANCI.

145 ive protein complex with FANCD2 and protects FANCD2 from proteasomal degradation.

146 Once recruited, FANCD2 fulfills a dual role towards replication fork rec

147 tasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair.

148 rt that FA complementation group D2 protein (FANCD2) functionally impacts mitochondrial ATP productio

149 The full repertoire of Fancd2 functions in normal development and tumorigenesis

150 a pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1.

151 Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we

152 Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased se

153 Our results reveal that FANCD2 has a ubiquitination-independent role in counteri

154 Importantly, FANCD2 has additional independent functions: it binds ch

155 We propose that FANCI and FANCD2 have partially non-overlapping and possibly even

156 se is in the monoubiquitination of the FANCI-FANCD2 heterodimer, a central step in the Fanconi anemia

157 n interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA.

158 n this study, we identify and characterize a FANCD2 histone-binding domain (HBD) and embedded methyl-

159 21 promotes S-phase and DNA damage-inducible FANCD2/I monoubiquitination and nuclear foci formation.

160 The cellular regulation of FANCD2/I monoubiquitination, however, remains poorly und

161 ited to lesions by a monoubiquitinated FANCI-FANCD2 (ID) complex and participates in ICL repair.

162 CtIP binds and stabilizes FANCD2 in a DNA damage- and FA core complex-independent

163 ctive CA-FOXO3a and WT or a nonubiquitinated Fancd2 in dKO bone marrow stem/progenitor cells, we demo

164 vely, our study demonstrates a novel role of FANCD2 in governing cellular ATP production, and advance

165 Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous

166 itive to acetaldehyde, supporting a role for FANCD2 in repair of lesions induced by such endogenous m

167 dogenous recombination events and implicates FANCD2 in the promotion of recombination-mediated repair

168 reduced in UM and that ectopic expression of FANCD2 increased SCE.

169 emia (FA) pathway, such as FANCJ, BRCA1, and FANCD2, interact with mismatch repair (MMR) pathway fact

170 o DNA repair partners, we observed that many Fancd2-interacting proteins are mitochondrion-specific.

171 mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interact

172 ls, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance.

173 r, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair.

174 Fancd2 is a component of the Fanconi anemia (FA) DNA rep

175 In contrast, isolated FANCD2 is a homodimer that is unable to bind DNA, sugges

176 We show that FANCD2 is an essential regulator of BLMcx functions: it

177 , but we show that recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair.

178 Mono-ubiquitination of Fancd2 is essential for repairing DNA interstrand cross-

179 In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced D

180 Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2

181 Surprisingly, although FANCD2 is required for this enhanced interaction, its mo

182 f FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitmen

183 ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand cr

184 ic FA proteins coordinately monoubiquitinate FANCD2, it is unclear why losses of individual classic F

185 Mutation of the monoubiquitination site of FANCD2 (K561R) preserves interaction with FANCJ constitu

186 relationship was not observed in the mutant FANCD2 (K561R)-carrying cells.

187 e developed a Flag- and hemagglutinin-tagged Fancd2 knock-in mouse strain that allowed a high through

188 pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 d

189 Also, FANCB is required for FANCD2 localization during meiosis, suggesting that the

190 ATRX and FANCD2 localize to stalled replication forks where they

191 Fancd2 localizes in the mitochondrion and associates wit

192 The central FA pathway protein, FANCD2, locates to stalled replication forks and recruit

193 Additionally, FANCD2 loss stimulates HPV genome amplification in diffe

194 Together, these data suggest FANCD2 may promote spontaneous SCE by influencing which

195 nostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance.

196 Fancd2 (-/-) mice developed hepatobiliary disease and ex

197 Upon Paigen diet challenge, male Fancd2 (-/-) mice had altered expression of genes encodi

198 In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients

199 T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than thos

200 Adh5(-/-)Fancd2(-/-) mice reveal an essential requirement for the

201 one, by improving peripheral blood counts in Fancd2(-/-) mice significantly faster.

202 ally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the

203 hematopoiesis and delays tumor formation in Fancd2(-/-) mice.

204 The Atad3-Tufm complex is disrupted in Fancd2-/- mice and those deficient for the FA core compo

205 Fancd2 mitochondrial localization requires Atad3.

206 repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and

207 ry fibroblasts, Helq(gt/gt) cells had intact FANCD2 mono-ubiquitination and focus formation.

208 embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment.

209 Residual FANCD2 monoubiquitination activity is retained in cells

210 ty is associated with the extent of residual FANCD2 monoubiquitination activity.

211 role in PCNA monoubiquitination and TLS in a FANCD2 monoubiquitination and HR-independent manner in r

212 g missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-bas

213 ired to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggestin

214 een FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro.

215 FANCI:FANCD2 monoubiquitination is a critical event for replic

216 complex-independent manner, suggesting that FANCD2 monoubiquitination is dispensable for its interac

217 mentation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity

218 Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favo

219 Importantly, FANCD2 monoubiquitination within the ID2 complex is stro

220 sslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi ane

221 FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repa

222 efects in early FA genes with the absence of FANCD2 monoubiquitination.

223 everity is associated with level of residual FANCD2 monoubiquitination.

224 A binding activity compromise DNA-stimulated FANCD2 monoubiquitination.

225 re complex and biochemical reconstitution of FANCD2 monoubiquitination.

226 ro to study functional consequences of FANCI:FANCD2 monoubiquitination.

227 e integrity of the FA core complex, and thus FANCD2 monoubiquitination.

228 oved their resistance to MMC re-establishing FANCD2 monoubiquitination.

229 tion, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination.

230 roliferating cell nuclear antigen (PCNA) and FANCD2 monoubiquitinations (surrogate markers of TLS and

231 116-OxR) cells and that gammaH2AX, PCNA, and FANCD2 monoubiquitinations are induced by oxaliplatin in

232 In the absence of FANCD2, MRE11 exonuclease-promoted access of FAN1 to sta

233 Intriguingly, analogous to FANCD2-mUb and BRCA1/BRCA2, REV1 plays an unexpected rol

234 mbly at laser-damaged sites, suggesting that FANCD2-mUb functions downstream of RAD18 to recruit REV1

235 , on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1.

236 Here we report that aged Aldh2(-/-) Fancd2(-/-) mutant mice that do not develop leukaemia sp

237 Brca2 deficiency but not in conjunction with Fancd2 mutation.

238 complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous

239 Rescue by Msh2 loss was confirmed in Fancd2-null primary mouse cells.

240 FANCJ is necessary for efficient loading of FANCD2 onto chromatin following DNA damage caused by mit

241 binding of BRCA1 to BARD1, PALB2, BRCA2 and FANCD2, phosphorylation of p53 or BRCA1 nuclear localiza

242 e reduced in UM and PD20 cells compared with FANCD2-proficient cells.

243 This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show that recruitment

244 We propose that, in ALT cells, FANCD2 promotes intramolecular resolution of stalled rep

245 Our data demonstrate that FANCD2 protein is required to ensure efficient CFS repli

246 e complex monoubiquitinates and recruits the FANCD2 protein to ICLs on chromatin.

247 biquitination and recruitment of the central FANCD2 protein to sites of stalled replication forks.

248 itical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are defi

249 se activation involves ubiquitylation of the FANCD2 protein.

250 ted Fanconi anemia complementation group D2 (FANCD2) protein in the Fanconi anemia pathway of the DNA

251 Both FANCI and FANCD2 proteins co-localized with RPA along meiotic chro

252 uitinates and recruits the central FANCI and FANCD2 proteins that subsequently coordinate ICL removal

253 ogenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for

254 roup L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection counteri

255 FANCD2, RAD51 and RAD18 form a complex, which is enhance

256 ctivation, respectively) and with attenuated FANCD2, RAD6, gammaH2AX, and POL eta foci formation and

257 t with a replication inhibitor, aphidicolin, FANCD2 recruits CtIP to transiently stalled, as well as

258 In addition, we also found that FANCD2 reduces the number of potential sites of replicat

259 ion and provide mechanistic insight into how FANCD2 regulates CFS stability.

260 Our results suggest not only that FANCD2 regulates FANCJ chromatin localization but also t

261 FANCD2 relocalized to viral replication compartments, an

262 a-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromoso

263 In the absence of FANCD2, replication forks stall within the AT-rich fragi

264 Depletion of FANCD2 results in a hyper-ALT phenotype, including an in

265 FANCD2's ubiquitination-independent function is likely i

266 stalled replication forks, monoubiquitinated-FANCD2 serves to recruit DNA repair proteins that contai

267 tion is decreased in FANCD2 deficient cells, FANCD2 siRNA knockdown cells and RAD51 siRNA knockdown c

268 ered significantly in abundance depending on Fancd2 status in male mice.

269 mpacted by Paigen diet feeding regardless of Fancd2 status.

270 that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human kerat

271 -FANCI adopts a closed conformation when the FANCD2 subunit is monoubiquitinated, creating a channel

272 ping requires monoubiquitination of only the FANCD2 subunit.

273 n cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is r

274 How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown.

275 o maintain telomeres, a process that we show FANCD2 suppresses.

276 FA complementation group I and D2 (FANCI and FANCD2) that function as part of the FA I-D2 complex, in

277 way, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to r

278 ted proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2), the WRN-1 or HIM-6 (BLM) helicases, or the GEN-

279 FANCD2, the central protein of the FA pathway, is monoub

280 ough mutation of the CUE domain destabilizes FANCD2, the protein remains competent for DNA damage-ind

281 Monoubiquitinated FANCD2 then recruits additional protein factors to remov

282 key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcript

283 At stalled forks, CtIP cooperates with FANCD2 to promote fork restart and the suppression of ne

284 e that ATRX is a novel functional partner of FANCD2 to promote histone deposition-dependent HR mechan

285 Lastly, ATRX also cooperates with FANCD2 to promote the HR-dependent repair of directly in

286 In tumor-prone Fancd2(-/-)Trp53(+/-) mice, metformin delayed the onset

287 or the FAN1 UBZ domain, indicating that the FANCD2(Ub) isoform is dispensable for functional FANCD2-

288 s selectively with monoubiquitinated FANCD2 (FANCD2(Ub)) at ICLs.

289 Moreover, Fancd2-Ub activates the transcription of the tumor suppr

290 For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their

291 Expression of a FANCD2-Ub chimeric protein in RAD18-depleted cells enhan

292 mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors.

293 ir of DNA double-strand breaks, hinting that FANCD2 utilizes HR proteins to mediate replication fork

294 to MMC and MMC-induced monoubiquitination of FANCD2 was impaired.

295 stem/progenitor cells, we demonstrated that Fancd2 was required for nuclear retention of CA-FOXO3a a

296 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined F

297 th FANCI and the epistatic relationship with FANCD2, we created the first conditional inactivation mo

298 so induced accumulation of monoubiquitinated FANCD2, which is recruited to stalled replication forks

299 ing to the interaction between ATP5alpha and FANCD2, which was confirmed by protein docking analysis.

300 Here, we describe the direct interaction of FANCD2 with FANCJ.