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HAT Histone Acetyl Transferases Attività anomale da parte degli enzimi HDACs sono state evidenziate in molti diversi tipi di cancro, come la leucemia promielocitica,

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Presentation on theme: "HAT Histone Acetyl Transferases Attività anomale da parte degli enzimi HDACs sono state evidenziate in molti diversi tipi di cancro, come la leucemia promielocitica,"— Presentation transcript:

1 HAT Histone Acetyl Transferases Attività anomale da parte degli enzimi HDACs sono state evidenziate in molti diversi tipi di cancro, come la leucemia promielocitica, la leucemia mielogena acuta, il linfoma di non-Hodgkin, e altri tipi di carcinomi colorettali e gastrici. Quando questi enzimi agiscono in modo "scorretto," possono impedire la trascrizione di geni fondamentali. 3 HAT Families

2 KAT3 Family: p300 (E1Abinding protein) and CBP(CREB binding protein)

3 Rubinstein–Taybi syndrome (RTS) is a developmental disorder caused by heterozygous germline mutations (point mutations, translocations or deletions) of the CBP gene. RTS is characterized by broad thumbs, cranio-facial and cardiac abnormalities, as well as mental retardation. Patients with RTS have an increased predisposition to cancer P300/CBP in cancer M4/M5 subtype of acute myeloid leukemia (AML) This translocation fuses the gene encoding the monocytic leukemia zinc- finger protein (MOZ) with the amino terminus of CBP. aberrant acetylation MLL-CBP and MLL-p300 translocations (MLL-mixed lineage leukemia) have also been described.(AML) aberrant acetylation and methylation Mutations in CBP or P300 are correlated with different type of tumors Chromosomal rearrangements involve CBP more commonly than p300.

4 HDAC- Histone Deacetylase Classe1: omologo yRPD3 (dominio HDAC,nucleari) Classe2: omologo yHDA1 (dominio HDAC, nucleari/citoplasmatiche(P)) Classe 3: ySIRT2 Classe 4:classificato per omologia di sequenza

5 HDAC- Histone Deacetylase Classe 2a: residui forforilati conservati molto importanti per il shuttling tra nucleo e cyt Classe 2b : ha due domini HDAC consecutivi

6 HDAC classe3 : Sir Sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD hydrolysislysinedeacetylationNAD Sir2 family deacetylation target consensus sequences. The amino acid sequence of the Sir2 targets are shown: histone H3 lysine 9; histone H3 lysine 14; histone H4 lysine 16; p53 lysine 382; Tubulin, alba.

7 PRMT and KMT: Methyl Transferases MLL importante nell leucemie infantili Interagisce con : WDR5, RBBP5, MEN1 e ASH2L

8 KMT: Lysin Methyl Transferases leukemia PRC2 No Set domain

9 KMT: SET domain ((Su(var)3-9, Enhancer of Zeste, Trithorax))

10 PRMT:Protein arginine methyltransfera ses Domini altamente conservati Motif I: VLD/EVGXGXG; Post I: V/IXG/AXD/E; Motif II: F/I/VDI/L/K; Double E Loop Motif III: LR/KXXG; THW loop

11 PRMT S-adenosilmetioninaadenosilomocisteina

12 KDM:Lysine Demethylase

13 H3K4me3 H3K9me3 H3K27me3 H3K36me1,2 KDM

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23 ASH2L: important for trymetilation of H3 K4 Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes Melissa M Steward1, Jung-Shin Lee1, Aisling ODonovan2,Matt Wyatt1, Bradley E Bernstein2 & Ali Shilatifard1,3 SEPTEMBER 2006 NATURE STRUCTURAL & MOLECULAR BIOLOGY MEN1

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27 Mistargeting of chromatin modifications occur as epigenetic lesions at MLL-AF4 target regions Guenther M. G. et.al. Genes Dev. 2008;22: ©2008 by Cold Spring Harbor Laboratory Press

28 Model of MLL-AF4-mediated gene activation in leukemia Guenther M. G. et.al. Genes Dev. 2008;22: ©2008 by Cold Spring Harbor Laboratory Press

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30 Liver Breast Colon SUZ12 Gastric Lung Endometrial Liver Skin Colon Bladder Myeloma Lymphoma Breast Prostate EZH2

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33 ProteinsProtein domainsFunctions Drosophila melanogasterHumanMouse PRC2 initiation complex ESCEED WD40 repeats * E(Z)EZH1EZH1/ENX2SET domain Histone methyltransferase EZH2EZH2/ENX1 SU(Z)12SUZ12 Zinc-finger domain PRC1 maintenance complex PCCBX2/HPC1CBX2/M33ChromodomainMethyl-lysine binding CBX4/HPC2CBX4/MPC2 CBX8/HPC3CBX8/PC3 PHEDR1/HPH1EDR1/MPH1/RAE28 Zinc-finger SPM domain § EDR2/HPH2EDR2/MPH2 EDR3/HPH3EDR3 RINGRING1/RNF1/RING1ARING1/RING1ARING-finger domain || Ubiquitin ligase RNF2/RING1B PSCBMI1 RING-finger domain || RNF110/ZFP144/ PCGF2RNF110/ZFP144/MEL18 ZNF134 PHOYY1 Zinc-finger domain Sequence-specific DNA binding PHO-like DNA binding SCMSCML1SCMH1 Zinc-finger SPM domain § PCLPHF1PHF1/PCL1PHD-finger domain

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36 Global perturbations of histones PTMs in human cancers. H3K4me2 (MLL) Prostate Seligson et al. Nature H3K20me3 Lymphoma Fraga et al. Nat Genet mouse SCC H3K18ac Prostate Seligson et al. Nature H3K16ac (MOF) Lymphoma Fraga et al. Nat Genet Breast, Medulloblastoma Pfister ey al. Int J Cancer H3K9me2 Prostate, Kidney Seligson et al. Am J Pathol Ellinger et al. Prostate H3K18ac Lung, Kidney Seligson et al. Am J Pathol Ellinger et al. Prostate H3K27me3 (Pg) Prostate Yu et al. Caner Res

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38 p300/CBP and cancer Narayanan Gopalakrishna Iyer 1, Hilal Özdag 1 and Carlos Caldas 1 1 Lysine methylation: beyond histones Xi Zhang, Hong Wen, and Xiaobing Shi


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