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Fanconi Anemia, Bloom Syndrome and Breast Cancer

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Fanconi Anemia, Bloom Syndrome and Breast Cancer A multiprotein complex in DNA damage response network of Fanconi anemia, Bloom syndrome and Breast cancer Weidong Wang Lab of Genetics, NIA A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia Bloom Syndrome . Genomic Instability: -sister-chromatid exchange . Cancer predisposition . Mutation in BLM, a RecQ DNA Helicase . BLM participates in: HR-dependent DSB repair Recovery of stalled replication forks . BLM works with Topo IIIa and RMI to Suppress crossover recombination Courtesy of Dr. Ian Hickson A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I l o r t n o BLM IP kDa C HeLa BLAP 250 Nuclear Extract 200- BLM* FANCA* 116- TOPO IIIα* 97- BLAP 100 MLH1* BLM IP BLAP 75 * 66- RPA 70 IgG H 45- * 30- RPA32 IgG L 20- * 12- RPA14 Meetei et al. MCB 2003 A Multi-protein Complex Connects Two Genomic Instability Diseases: Bloom Syndrome and Fanconi Anemia P I A C N A F BLM IP HeLa FANCM= FAAP 250 BLAP 250 Nuclear Extract BLM* BLM* * FANCA* FANCA TOPO IIIα* TOPO IIIα* FAAP 100 BLAP 100 FANCB= FAAP 95 MLH1 FANCA IP BLM IP BLAP 75 BLAP 75 RPA70*/FANCG* RPA 70* FANCC*/FANCE* IgG H FANCL= FAAP 43 FANCF* RPA32* IgG L Meetei et al. MCB 2003 Meetei et al. Nat Genet. 2003, 2004, 2005 BRAFT-a Multisubunit Machine that Maintains Genome Stability and is defective in Fanconi anemia and Bloom syndrome BRAFT Super-complex Fanconi Anemia Bloom Syndrome Core Complex Complex 12 polypeptides 7 polypeptides FANCA BLM Helicase (HJ, fork, D-loop), fork FANCC regression, dHJ dissolution Topo IIIα Topoisomerase, FANCE dHJ dissolution FANCF BLAP75 RMI1 FANCG Stimulates dHJ dissolution. Mediates protein-protein RMI2 FANCB interactions Ubiquitin ligase FANCL RPA70 Binds and translocates Binds ssDNA Branch point (4 WJ, fork) FANCM RPA34 dsDNA translocase Stimulates BLM helicase FAAP24 Stimulates dHJ dissolution Targets FANCM to RPA14 ssDNA MHF1 Targets FANCM to BLAP250 MHF2 dsDNA FAAP100 Fanconi Anemia: A multi-Gene Disease Model to Study Repair of Crosslinked DNA Damage and Function of BRCA Proteins • 13 complementation groups and genes – FANC-A,B,C,D1,D2,E,F,G,I, J, L,M,N • BRCA1 and BRCA2 connection – BRCA2=FANCD1 – PALB2=FANCN – BACH1/BRIP1=FANCJ • Cellular Hypersensitivity to DNA- crosslinking drugs – A model for studying repair of crosslinked DNA damage • Genomic Instability: – Chromosomal breaks and interchanges • Cancer predisposition: – Myeloblastic leukemia – Squamous cell carcinomas • Aging: Courtesy of Dr. Johan de Winter – Bone Marrow Failure – Skin abnormalities—look older Group I FA proteins constitute the FA core complex that has a E3 ubiquitin ligase and a DNA remodeling enzyme P FANCA Coiled-coil FANCB FANCC P FANCE Group I: FANCF FA Core TPR motifs P Complex FANCG ELF DRWD Ring Finger FANCL E3 ub ligase Helicase P ERCC4-like FANCM X DNA binding FAAP24 Histone-fold X & remodeling MHF1 & MHF2 FAAP100 Coiled-coil Group II FA proteins are monoubiquitinated by the FA core complex; Group III may act downstream of the FA pathway P Ub ARM repeats FANCD2 Group II: Partners FA ID P Ub ARM repeats complex FANCI BRC OB-fold Repeats DNA binding P FANCD1 (BRCA2) Group III: BRCA1 WD40 Repeats Partners FANCN association (PALB2) P FANCJ Helicase (BRIP1) Fanconi anemia core complex participates in monoubiquitination of FA ID complex through FANCL and DNA repair via FANCM FA pathway: MHF Xue HMG 2008 Switch USP1 p D1(BRCA2) p ATR N (PALB2) p J (BACH1) Vertebrate FANCM interacts with multiple repair and signaling partners to integrate signals from several pathways FANCM Helicase MM1 MM2 ERCC4 HCLK2 MHF FAAP24 FA Core BLM Top3/RMI dsDNA ATR Ub Bind ssDNA Binds branch point ATR (HJ, Fork) dHJ dissolution Checkpoint HR repair (Chk1-P) Ub-FANCD2 Fork reversal Branch point Ub-FANCI Remodeling Repair of Interstrand Crosslinks SCE suppression FANCM-MHF may represent a minimal version of the FA core complex conserved in all eukaryotes Yeast and all eukaryotes Fanconi Anemia BLM/Sgs1 Core Complex Complex BLM SGS1 FANCM/ Topo IIIα MPH1/FML1 ?? BLAP75 MHF1 RMI1 MHF2 MHF1 and MHF2 Are New Components of the FA Core Complex FANCM IP FANCM 200 HeLa BLM Nuclear Extract FANCA 116 TOPIIIα 97 FAAP100 BLAP75 RPA70 66 FANCG Superose 6 FANCC&E 55 fractionation 36 FANCF 31 RPA32 FAAP24 FANCM IP 21 MHF1 14 MHF2 6 (Yan et al. Mol Cell in press) MHF1/2: FANCM -associated Histone Fold protein 1 and 2. MHF1 and MHF2 Are New Components of the FA Core Complex MHF1 IP FANCM-associated Proteins HeLa FANCM MHF 200 24 Nuclear Extract BLM FANCM FANCA A BLM 116 TOPIIIα 97 FAAP100 G TopIIIα BLAP75 C RMI1 Superose 6 66 RPA70 FANCG E RMI2 fractionation 55 FANCC&E F RPA 36 FANCF B 31 RPA32 L FAAP24 100 MHF IP 21 MHF1 14 MHF2 FA-core BLM 6 complex complex MHF1 and MHF2 can also form a complex without FANCM BRAFT MHF 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 FANCM MHF1 MHF2 670 440 232 158 kDa x le p m o 1 2 c F F F MHF1 IP H H H M M - - -M S S S HI HI HI 200 116 97 66 X 55 36 31 21 MHF1 MHF1 14 MHF2 MHF2 6 MHF is identical to the CENP-S complex and Binds dsDNA Histone-fold MHF complex (CENP-S complex) MHF1/CENP-S α1 α2 α3 138 aa MHF1 MHF2 MHF2/CENP-X α1 α2 α3 81 aa Amano et al. JCB 2009 ssDNA dsDNA * * MHF MHF _ _ MHF1 MHF2 MHF2 MHF1 * MHF MHF provides a complementary DNA binding interface for FANCM-FAAP24 to recognize stalled forks Helicase ERCC4 FANCM MHF FAAP24 Branch dsDNA point ssDNA MHFFANCM FAAP24 MHF recruits FANCM to dsDNA Helicase MHF ERCC4 FANCM Helicase MHF FANCM-N _ _ rFANCM-N _ _ _ _ + + + + MHF * MHF M-N * MHF * FANCM and MHF binds DNA synergistically _ _ MHF _ _ MHF _ _ _ _ _ _ _ _ + + + + + + + + rFANCM-N rFANCM-N * MHF M-N * MHF M-N * Fork * HJ Most FANCM-MHF is present in a complex that is largely free of other FA core complex components MHF1 IP HeLa Nuclear Extract FANCM 200 116 MHF1 IP 97 66 55 36 31 21 14 MHF1 6 MHF2 A large percentage of FANCM-MHF is present in a complex independent of the FA core complex MHF1 IP MHF and FANCM Form a DNA remodeling Complex that Protects Genome Stability from Human to Yeast <30% of FANCM-MHF Most FANCM-MHF Vertebrates Only All eukaryotes Reconstituted FANCM-MHF has Higher Replication Fork Reversal Activity than FANCM alone MHF FANCM FANCM FANCM can catalyze fork regression b b Reversal FANCM + MHF FANCM b b (b) ( Dr. Angelos Constantinou Lab ) MHF Is Required for stability and chromatin association of FANCM MHF Is Required for Normal Monoubiquitination of FANCD2-FANCI and cellular resistance to MMC in human HeLa cells MMC Cisplatin (siRNA) 1 0.8 Control Control MHF2 MHF2 Control MHF2 siControl FANCD2 L S 0.6 L FANCI 0.4 S Survival (%) 0.2 siMHF2 MHF2 0 ACTIN 0 100 200 300 400 500 600 MMC (ng/ml) FANCM and MHF Are Rapidly Recruited to DNA Interstrand Crosslinks induced by Laser-activated Psoralen in S-phase cells S-phase HeLa cells+ laser-activated psoralen ~1 5 15 30 45 min FANCM MHF1 - FANCM-MHF is recruited to replication forks blocked by ICLs Mike Seidman’s group FANCM Recruitment to replication forks stalled by laser- induced ICLs is disrupted in MHF-depleted cells γ-H2AX FANCM Merged siControl siMHF1 siMHF2 M. Seidman’s group eCHIP—A new method to directly detect proteins recruited to DNA interstrand crosslinks in cells (Lei Li’s group; Shen et al. Mol. Cell 2009) MHF1 is recruited to DNA interstrand crosslinks; and its recruitment is stimulated by replication Lei Li’s group MHF and FANCM Work in the Same Pathway to Promote FANCD2 Monoubiquitination and to Suppre DT40 cells: L/S: 1.54 WT ss SCE in chicken DT40 cells -/ MHF1 - 0.34 0.16 0.16 -/- FANCM -/- MHF1 -/- FANCM MHF complex containing mutant A lacks DNA binding activity mut AB mut A mut B AA AA KR RR MHF1 α1 α2 α3 Histone-fold MHF complex WT Mut A WT Mut A WT Mut A + + + + 220 120 70 50 * 40 MHF 30 25 20 MHF1 10 His-MHF2 * MHF containing mutant A lacks DNA binding activity and fails to recruit FANCM to fork DNA MHF FANCM-N MHF MHF M-N MHF The MHF1 mutant A has normal association with MHF2 and FANCM, whereas mutant B and AB have reduced association MHF1 Requires its DNA binding activity to Promote normal FANCD2 Monoubiquitination MHF1 B A B A t t t ut u u WT m m MHF1-/- w m + + + + + + MMC FANCD2-L FANCD2-S L/S: 0.99 0.21 0.82 0.43 0.55 0.19 FANCM 1 0.44 1.9 1.9 1.2 0.4 MHF1 MHF2 BAF57 MHF1 Requires its DNA binding activity to efficiently Suppress Sister-Chromatid Exchange 28 24 9.7 9.9 20 16 7.1 6.3 12 2.5 2.9 8 4 0 WT wt mut A mut B mut AB MHF1-/- Yeast MHF and FANCM Work in the Same Pathway to resist MMS-induced cell killing MHF1 MHF2 Mph1 (FANCM) S. cerevisiae untreated 0.1% MMS Cell number wt mhf1∆ mhf2∆ mph1∆ mph1∆mhf1∆ mph1∆mhf2∆ (srs2∆ strain) ( Dr. Kyungjae Myung Lab ) The FANCM ortholog in S.
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