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The Methylation Cycle

The Methylation Cycle. Cytosine and dervatives. Synthesis of SAM. SAM is the methyl donor in biological rxn-s. DNA with cytosine flipped-out in MMT complex. DNA and DNA-methyltransferase comlex. Epigeneti kai változások = genom met iláció.

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The Methylation Cycle

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  1. The Methylation Cycle

  2. Cytosine and dervatives

  3. Synthesis of SAM SAM is the methyl donor in biological rxn-s

  4. DNA with cytosine flipped-out in MMT complex

  5. DNA and DNA-methyltransferase comlex

  6. Epigenetikaiváltozások = genom metiláció kb. az összes daganatok 65%-ában metilációs rendellenesség mutatható ki http://www.epigenx.com/methylation-cancer.htm

  7. DNS metiláció mutációt okozhat a humán genombana számítottnál kevesebbCpG dinukleotid van,feltehetően az 5-metilcitozin timinné (U) történődezaminációjánakkövetkeztében

  8. Promoter/enhancer repression and repressor activation by imprint imprinted allele is silent imprinted allele is active

  9. Clustered imprinted genes

  10. CpG dinukleotidotmetiltranszferázok metilálják DNMT1– fenntartja a DNS metilációs mintázatát új DNS szintézisét követően DNMT 3a and 3b– ‘de novo’ metiltranszferázok normális, hogy a CpG dinukleotidok metilálódnak a genom kb. 30 000 nem-metilált CpG ‘sziget’-et tartalmaz 50–60%-bangénekkel asszociált általában azok promoter régiójában CpG szigetek normálisan nem metilálódnak (!)

  11. Human CpG-island genes CpG-s in the first 10 kbase

  12. Distribution of CpG islands in the human genome red: CpG island green: late-replicating DNA

  13. DNSmetilázokdaganatsejtekben • DNMT1 mRNS(‘maintenance’ methylation)csökkent !!! • DNMT-3b mRNS(a CpG szigetek ‘de novo’ metilációja) megnövekedett !!! • ez magyarázza a paradoxont: • globálishipometiláció • a CpG szigetekhipermetilációja DNMT-3b a daganatterápia egyik ‘moleculáris célpontja’ (a TSG-k funkciójának visszaállítására)

  14. Epigenetic and genetic interactions in tumorigenesis MLH1 mismatch repair: MIN+ p16INK4a cdk inhibitor: bypass of the early mortality checkpoint Mo GSTP1 glutathione S transferase: oxidative DNA damage

  15. Promoter CpG island hypermethylationin sporadic cancers Gene Function Tumor familiar, tumor suppressor genes VHL angiogenesis RCC p16 cdk inhibitor solid lymphomas E-cad cell adhesion breast, thyroid, etc. MLH1 mismatch repair colon, gastr, endometr BRCA1 damage repair breast, ovarial LKB1 ser/thr kinase colon, breast other proliferation-related genes p15 cdk inhibitor AML, ALL ER estrogen receptor TF breast, colon, leukemias O6MGMT repair of guanosine brain, colon, lung, lymph. methyl adducts GSTPI prevention of oxidative breast, prostate, renal DNA damage TIMP3 inhibitor of tissue colon, renal, brain metalloproteases DAPK1 IF-induced apoptosis BCL, lung p73 p53-like gene lymphomas

  16. nuclosome with deacetylated histones, HAT: histone acetylase, CA: co-activator, TF: transcription factors, DNMT: DNA methyl transferase, MBP: methyl cytosine binding proteins, HDAC: histone de-acetylases Methylation in normal and cancer cell normal cancer

  17. normal Promoter methylation in normal and cancer cell tumor A1,A2,A3: activators, HDAC: histone deacetylase, R1,R2,SIN3: repressors, CBP: cAMP-response binding, MBP: methyl cytosine binding protein

  18. Disease-causing mutations in DNMT3b and MeCP2 Rett syndrome (a) ICF: immunodeficiency, centromeric instability and facial anomalies syndrome (b) Rett syndrome: X-linked mental retardation

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