HATHistone 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

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

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 alsobeen 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.

HDAC-Histone Deacetylase

Classe1: omologo yRPD3 (dominio HDAC,nucleari)Classe2: omologo yHDA1(dominio HDAC, nucleari/citoplasmatiche(P))Classe 3: ySIRT2Classe 4:classificato per omologia di sequenza

HDAC-Histone Deacetylase

Classe 2a: residui forforilati conservati molto importanti per il shuttling tra nucleo e cytClasse 2b : ha due domini HDAC consecutivi

HDAC classe3 : Sir

Sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD hydrolysisSir2 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.

PRMT and KMT: Methyl Transferases

MLL importante nell leucemie infantiliInteragisce con : WDR5, RBBP5, MEN1 e ASH2L

KMT: Lysin Methyl Transferases

leukemia

PRC2

No Set domain

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

PRMT:Protein arginine methyltransferases

Domini altamente conservatiMotif 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

PRMT

S-adenosilmetionina adenosilomocisteina

KDM:Lysine Demethylase

H3K4me3

H3K9me3

H3K27me3

H3K36me1,2

KDM

ASH2L: important for trymetilation of H3 K4

Molecular regulation of H3K4 trimethylation by ASH2L,

a shared subunit of MLL complexesMelissa M Steward1, Jung-Shin Lee1, Aisling O’Donovan2,Matt Wyatt1,

Bradley E Bernstein2 & Ali Shilatifard1,3SEPTEMBER 2006 NATURE STRUCTURAL & MOLECULAR

BIOLOGY

MEN1

MEN1

MEN1

Mistargeting of chromatin modifications occur as epigenetic lesions at MLL-AF4 target regions

Guenther M. G. et.al. Genes Dev. 2008;22:3403-3408

©2008 by Cold Spring Harbor Laboratory Press

Model of MLL-AF4-mediated gene activation in leukemia

Guenther M. G. et.al. Genes Dev. 2008;22:3403-3408

©2008 by Cold Spring Harbor Laboratory Press

Liver

Breast

ColonSUZ12

Gastric

Lung

Endometrial

Liver

Skin

Colon

Bladder

Myeloma

Lymphoma

Breast

Prostate EZH2

Proteins Protein domains Functions

Drosophila melanogaster Human Mouse    

PRC2 initiation complex

ESC EED EED WD40 repeats*  

E(Z) EZH1 EZH1/ENX2 SET domain‡ Histone methyltransferase

  EZH2 EZH2/ENX1    

SU(Z)12 SUZ12 SUZ12 Zinc-finger domain  

PRC1 maintenance complex

PC CBX2/HPC1 CBX2/M33 Chromodomain Methyl-lysine binding

  CBX4/HPC2 CBX4/MPC2    

  CBX8/HPC3 CBX8/PC3    

PH EDR1/HPH1 EDR1/MPH1/RAE28Zinc-finger SPM domain§  

  EDR2/HPH2 EDR2/MPH2    

  EDR3/HPH3 EDR3    

RING RING1/RNF1/RING1A RING1/RING1A RING-finger domain|| Ubiquitin ligase

  RNF2/RING1B RNF2/RING1B    

PSC BMI1 BMI1 RING-finger domain||  

  RNF110/ZFP144/ PCGF2 RNF110/ZFP144/MEL18    

  ZNF134 ZNF134    

PHO YY1 YY1 Zinc-finger domainSequence-specific DNA binding

PHO-like       DNA binding

SCM SCML1 SCMH1Zinc-finger SPM domain§  

PCL PHF1 PHF1/PCL1 PHD-finger domain  

Global perturbations of histones PTMs in human cancers.

H3K4me2 (MLL) Prostate Seligson et al. Nature. 2005.

H3K20me3 Lymphoma Fraga et al. Nat Genet. 2005.

mouse SCC

H3K18ac Prostate Seligson et al. Nature. 2005.

H3K16ac (MOF) Lymphoma Fraga et al. Nat Genet. 2005.

Breast, Medulloblastoma Pfister ey al. Int J Cancer 2008.

H3K9me2 Prostate, Kidney Seligson et al. Am J Pathol. 2009.Ellinger et al. Prostate 2010.

H3K18ac Lung, Kidney Seligson et al. Am J Pathol. 2009.Ellinger et al. Prostate 2010.

H3K27me3 (Pg) Prostate Yu et al. Caner Res. 2007.

p300/CBP and cancerNarayanan Gopalakrishna Iyer1, Hilal Özdag1 and Carlos Caldas1

Lysine methylation: beyond histonesXi Zhang, Hong Wen, and Xiaobing Shi