einführung in die genetik - tum

Einführung in die Genetik

Prof. Dr. Kay Schneitz (EBio Pflanzen)http://[email protected]

Prof. Dr. Claus Schwechheimer (PlaSysBiol)http://wzw.tum.de/[email protected]

Thursday, January 31, 13

http://plantdev.bio.wzw.tum.de




mailto:[email protected]

mailto:[email protected]

Einführung in die Genetik - InhalteEinführung in die Genetik - InhalteEinführung in die Genetik - Inhalte1 Einführung 16. 10. 12 KS2 Struktur von Genen und Chromosomen 23. 10. 12 KS3 Genfunktion 30. 10. 12 KS4 Transmission der DNA während der Zellteilung 06. 11. 12 KS5 Vererbung von Einzelgenveränderungen 13. 11. 12 KS6 Genetische Rekombination (Eukaryonten) 20. 11. 12 KS7 Genetische Rekombination (Bakterien/Viren) 27. 11. 12 KS8 Rekombinante DNA-Technologie 04. 12. 12 CS9 Kartierung/Charakterisierung ganzer Genome 11. 12. 12 CS

10 Genmutationen: Ursache und Reparatur 18. 12. 12 CS11 Veränderungen der Chromosomen 08. 01. 13 CS12 Genetische Analyse biologischer Prozesse 15. 01. 13 CS13 Transposons bei Eukaryonten 22. 01. 13 CS14 Regulation der Genexpression 29. 01. 13 KS15 Regulation der Zellzahl - Onkogene 05. 02. 13 CS


Regulation of Gene Expression

Genetics 14


Summary• Cells respond to intrinsic and extrinsic signals by modulating

transcriptional control of certain genes

• Gene activity is the result of the function of cis- and trans-acting factors

• Trans-acting proteins react to environmental signals by using built-in sensors that continually monitor cellular conditions

• Coordinated gene regulation in bacteria

• genes are often clustered into operons on the chromosome and transcribed together as multigenic mRNAs

• one cluster of regulatory sites per operon is sufficient to regulate expression of several genes

• Negative vs positive regulation

• repressor proteins bind to DNA at operator site thereby blocking transcription (e.g., lac operon)

• activator proteins activate transcription by binding to DNA at the promoter region (e.g., cAMP/CAP regulation of lac operon)

• Molecular anatomy of genetic switch

• regulatory proteins have DNA-binding domains (e.g., HLH) and protein-protein interaction domains (modular

• specificity of gene regulation depends on specific protein-DNA interactions mediated by the chemical interactions between aa side chains and chemical groups of DNA bases


Summary• Eukaryotic gene regulation resembles bacterial gene regulation

• trans-acting factors binding to cis-regulatory elements on the DNA

• this regulatory factors determine the level of transcription by regulating the binding of RNA pol II to the promoter of a gene

• Enhancers/UAS

• cis-regulatory elements, possibly located quite far away (>10-50kb) from promoter

• combinatorial interactions among different transcription factors

• enhanceosome: complexes of regulatory proteins that interact in cooperative and synergistic fashion --> high levels of transcription through recruitment of RNA pol II

• Gene regulation and chromatin

• eukaryotic genes are packed in chromatin

• activation/repression requires specific modifications to chromatin

• genes are mostly turned off and kept silent in part by nucleosomes and condensed chromatin

• histone code: pattern of posttranslational modifications of histone tails (acetylation, methylation, phosphorylation etc).

• histone code is an epigenetic mark involved in nucleosome positioning and chromatin condensation that can be altered by TFs

• TFs recruit for example ATP-dependent chromatin remodelers (e.g., SWI-SNF)


Control of cell number - oncogenes

Genetics 15


Tumors

The cell cycle

Apoptosis

Cancerogenesis

The ubiquitin-proteasome system


Tumors

malignant vs. benign tumors

uncontrolled cell divisions and growth

invasion and colonization of tissue

metastasis


Tumor types

carcinoma - epithelial cell cancer

sarcoma - connective tissue or muscle cancer

leukemia or lymphoma - blood cell cancers

others


Tumors - incidence rates


Tumors - types and distribution


The cell cycle


FACS sorting (fluorescence activated cell sorting)

Cell cycle studies


Cell cycle studiesNorthern blot

Western blot


Cell cycle mutants of yeast


Temperature sensitive mutants in cell cycle analysis


Major check points in cell cycle control


Cell cycle studiesNorthern blot

Western blot


Cyclins and cyclin-dependent kinases are differentially transcribed throughout the cell cycle


Cyclins and cyclin-dependent kinases (CDKs)

Cyclin-CDK ! Vertebrates ! ! Yeast!Complex !Cyclin ! Cdk ! !Cyclin ! Cdk!

G1-Cdk ! !Cyclin D Cdk4, Cdk6 !Cln3 ! Cdk1!G1/S-Cdk !Cyclin E! Cdk2 ! !Cln1,2 ! Cdk1!S-Cdk ! !Cyclin A ! Cdk2 ! !Clb5,6 ! Cdk1!M-Cdk ! !Cyclin B! Cdk1 ! !Clb1,2,3,4 Cdk1!


Cyclin-CDK complexes control the cell cycle


Mitosis promoting factor and cyclins


Cell cycle control by Cyclin-CDKs


Cyclins and CDKs in cell cycle control


Mitotic cyclins and protein phosphorylation


The ubiquitin-proteasome systemand protein degradation


The ubiquitination machinery

E1 ubiquitin activating emzyme

E2 ubiquitin conjugating emzyme

E3 ubiquitin ligase


The ubiquitination machinery


The 26S proteasome


Mitotic cyclins and protein degradation


The anaphase promoting complex (APC)


Cancerogenesis


Major check points in cell cycle control


Examples for receptors in signaling


Receptor tyrosine kinases

JAK/STAT pathwayThursday, January 31, 13

Receptor tyrosine kinases

Growth factors (EGF, TGF etc.)


Ras


The Retinoblastoma (RB) tumor suppressor


Retinoblastoma protein (Rb) blocks E2F


Prelavance of p53 tumour-suppressor mutations


p53 is phosphorylated in responseto DNA damage


p53 phosphorylation blocks the cell cycle


p53 phosphorylation blocks the cell cycle

p53 +/+

daysThursday, January 31, 13

Mutations can induce cancer

RasRb

p53


Summary• Tumours are the result of uncontrolled

and invasive cell divisions and cell growth

• The cell cycle is governed by cyclins and cyclin-dependent kinases

• Cyclins and cyclin-dependent kinases are under transcriptional control

• Cyclins are degraded by the UPS

• E1, E2, E2 enzymes and ubiquitin

• 26S proteasome

• Apoptosis regulated cell number

• Apoptosis is a controlled process

• p53, RB and Ras are important cell cycle regulators


The end


einführung in die genetik - tum

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