ライフサイエンスコーパス: FANCD2

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

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

3 ntify CtIP as a novel interaction partner of FANCD2.

4 vating this pathway is monoubiquitination of FANCD2.

5 y of the complex and by directly recognizing FANCD2.

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

7 e effect of EGFR mutation was epistatic with FANCD2.

8 ATM-Chk2 checkpoint activation by sustaining FANCD2.

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

10 n cells that carry the non-monoubiquitinated FANCD2.

11 t the structure, function, and regulation of FANCD2.

12 he interaction with and chromatin loading of FANCD2.

13 telangiectasia and Rad3-related), FANCI, and FANCD2.

14 forks by homologous recombination, Rad51 and FANCD2.

15 se as assessed by detection of gammaH2AX and FANCD2.

16 lament formation in cells lacking functional FANCD2.

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

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

19 ation because of downregulation of RAD51 and FANCD2.

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

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

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

23 erbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL

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

25 FANCD2 acts independently of previous S phases to promot

26 FANCD2 also functions during the replication stress resp

27 led replication forks independently of FANCI-FANCD2 and before DSB formation.

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

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

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

31 FANCD2 and FANCI are thought to form a functional hetero

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

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

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

35 I; moreover, monoubiquitination responses of FANCD2 and FANCI exhibit distinct DNA substrate specific

36 Our results suggest that FANCD2 and FANCI function separately at consecutive step

37 FANCD2 and FANCI function together in the Fanconi anemia

38 hich heterodimerization of monoubiquitinated FANCD2 and FANCI in chromatin is mediated in part throug

39 AD18-knockout cells display a unique lack of FANCD2 and FANCI localization to chromatin in exponentia

40 Monoubiquitinated FANCD2 and FANCI localize in chromatin-associated nuclea

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

42 way occurs via the monoubiquitination of the FANCD2 and FANCI proteins, targeting these proteins to d

43 gase activity of RAD18 in the recruitment of FANCD2 and FANCI to chromatin and the events leading to

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

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

46 Fanconi anemia (FA) pathway members, FANCD2 and FANCI, contribute to the repair of replicatio

47 thway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized t

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

49 plex, which monoubiquitinates its substrates FANCD2 and FANCI.

50 the covalent attachment of monoubiquitin to FANCD2 and FANCI.

51 -inducible accumulation of monoubiquitinated FANCD2 and FANCI.

52 itylation and chromatin localization of both FANCD2 and FANCI.

53 ubiquitylation and chromatin localization of FANCD2 and FANCI.

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

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

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

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

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

59 the present study, we show that RAD18 binds FANCD2 and is required for efficient monoubiquitylation

60 cation forks by binding to monoubiquitinated FANCD2 and is required for interstrand crosslink repair,

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

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

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

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

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

66 2 FA proteins, FA complementation group D2 (FANCD2) and FANCI.

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

68 ependent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication fork

69 gradation) ubiquitin-binding domain (UBD) in FANCD2, and demonstrate that the CUE domain mediates non

70 n with FANCI, retention of monoubiquitinated FANCD2, and FANCI in chromatin, and for efficient ICL re

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

72 ing of human FANCL with its partners, Ube2t, FANCD2, and FANCI.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

89 Following dissociation, FANCD2 binds replicating chromatin prior to-and independ

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

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

92 zation of critical repair factors, including FANCD2, BRCA1 and RAD51, to MMC-induced subnuclear foci.

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

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

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

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

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

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

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

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

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

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

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

104 s of staining for the Fanconi anemia protein FANCD2 (corrected Fisher's exact test, P < 0.0007).

105 hrough a noncovalent interaction between the FANCD2 CUE domain and monoubiquitin covalently attached

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

107 Fancd2 deficiency strongly promoted cytoplasmic localiza

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

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

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

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

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

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

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

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

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

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

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

119 NCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair.

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

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

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

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

124 me Aldh2 is essential for the development of Fancd2(-/-) embryos.

125 reover, the concentration of chromatin-bound FANCD2 exceeds that of FANCI throughout replication.

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

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

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

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

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

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

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

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

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

135 on is regulated or what the functions of the FANCD2-FANCI complex versus the monomeric proteins are.

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

137 phosphorylation is the molecular trigger for FANCD2-FANCI dissociation.

138 How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown.

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

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

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

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

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

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

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

146 ed sensitivity to mitomycin C and a delay in FANCD2 foci formation compared with their wild-type coun

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

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

149 tion, demonstrating functional separation of FANCD2 from FANCI.

150 pathway activation triggers dissociation of FANCD2 from FANCI.

151 t this interaction shields monoubiquitinated FANCD2 from polyubiquitination and proteasomal degradati

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

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

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

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

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

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

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

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

160 21 promotes S-phase and DNA damage-inducible FANCD2/I monoubiquitination and nuclear foci formation.

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

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

163 thway is the monoubiquitination of the FANCI-FANCD2 (ID) complex by the multiprotein "core complex" c

164 ponsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade o

165 he Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-i

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

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

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

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

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

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

172 ions epistatically to the central FA factor, FANCD2, in cellular survival after ICL damage and homolo

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

174 as phosphomimetic FANCI cannot interact with FANCD2, indicating that FANCI phosphorylation is the mol

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

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

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

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

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

180 Here we show that FANCD2 interacts with the MMR proteins MSH2 and MLH1.

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

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

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

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

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

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

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

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

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

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

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

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

193 and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predis

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

195 Fancd2 localizes in the mitochondrion and associates wit

196 Additionally, FANCD2 loss stimulates HPV genome amplification in diffe

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

198 Moreover, FANCD2-mediated fork protection is epistatic with RAD51

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

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

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

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

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

204 Lastly, Aldh2(-/-)Fancd2(-/-) mice spontaneously develop acute leukaemia.

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

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

207 the development of double-mutant (Aldh2(-/-)Fancd2(-/-)) mice.

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

209 Fancd2 mitochondrial localization requires Atad3.

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

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

212 Residual FANCD2 monoubiquitination activity is retained in cells

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

214 RAD51C is dispensable for ICL unhooking and FANCD2 monoubiquitination but is essential for HR, confi

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

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

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

218 Importantly, FANCD2 monoubiquitination within the ID2 complex is stro

219 RNF8 and FAAP20 are needed for efficient FANCD2 monoubiquitination, a key step of the FA network;

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

221 Dissociation coincides with FANCD2 monoubiquitination, which significantly precedes

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

223 A binding activity compromise DNA-stimulated FANCD2 monoubiquitination.

224 re complex and biochemical reconstitution of FANCD2 monoubiquitination.

225 agents, chromosome aberrations, and reduced FANCD2 monoubiquitination.

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

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

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

229 116-OxR) cells and that gammaH2AX, PCNA, and FANCD2 monoubiquitinations are induced by oxaliplatin in

230 FANCD2 monoubiquitylation, foci formation and chromatin

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

232 ts suggest an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair.

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 further exacerbated upon depletion of either FANCD2 or another key FA protein, FANCI.

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

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

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

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

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

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

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

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

250 se activation involves ubiquitylation of the FANCD2 protein.

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

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

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

254 n be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed b

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 BRCA2, or RAD51, but not Chk1, ATM, PTEN, or FANCD2, sensitizes cells to ABT-888, and 3) demonstrate

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

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

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

270 How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown.

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

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

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

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

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

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

277 x deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and D

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

279 uired for recruitment of FA core complex and FANCD2 to ICLs, whereas RNF168 can modulate efficiency o

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

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

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

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

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

285 g of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinat

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

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

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

289 In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a

290 FANCD2 ubiquitylation is normal in cells containing a ub

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

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

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

294 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined F

295 hodead FANCI mutant fails to dissociate from FANCD2, whereas phosphomimetic FANCI cannot interact wit

296 to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities

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

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

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

300 Recombination acts downstream of FANCI-FANCD2, yet RAD51 binds ICL-stalled replication forks in