Biochemical and functional characterisation of the novel non-specific lethal complex [Elektronische Ressource] / vorgelegt von Iryna Charapitsa

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INAUGURAL - DISSERTATION


zur
Erlangung der Doktorwürde
der
Naturwissenschaftlich-Mathematischen Gesamtfakultät
der Ruprecht-Karls-Universität
Heidelberg























vorgelegt von
Iryna Charapitsa
aus Minsk, Weissrussland
Tag der mundlichen Prufung: 22 – 06 – 2009





DISSERTATION


submitted to the
Combined Faculties for the Natural Sciences and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany
for the degree of

Doctor of Natural Sciences






















Presented by

Iryna Charapitsa
Born in Minsk, Belarus
Date of oral examination: 22 - 06 - 2009















Biochemical and Functional
Characterisation of the Novel
Non Specific Lethal Complex




















st nd1 and 2 examiners

Dr. Anne Ephrussi
Prof. Dr. Gabriele Peterson

Main Supervisor: Dr. Asifa Akhtar






To my family





ACKNOWLEDGMENTS


I am thankful to Asifa for introducing me into the world of chromatin and being a
supportive inspiring supervisor, making the study presented in this thesis possible. It
is a pleasure to know you and work together.

I am grateful to my Thesis Advisory Committee members: Dr. Anne Ephrussi, Dr.
Lars Steinmetz and Prof. Gabriele Petersen for their useful input, guidance and
helpful motivating feedback.

Special thanks to my lab and colleagues at EMBL for creating an enthusiastic
working atmosphere that was driving our research.

I am deeply grateful to my friends and family, for their care and love.
1 Table of contents

SUMMARY………………………………………………………………….….….…6
ZUSAMMENFASSUNG………………………………………………………..……8
1. INTRODUCTION………………………………………………………………..10
1.1. Chromatin…………………………………………………………………..10
1.2. Chromatin organization…………………………………………….……..10
1.3. Chromatin dynamics and regulation of gene expression………….…….14
1.3.1. Nucleosome remodeling ………………………………….…….……14
1.3.1.1. SWI/SNF family……………………………….………….……15
1.3.1.2. ISWI family……………………………………..………………16
1.3.1.3. CHD family…………………………………..…………………18
1.3.1.4. INO80 and SWR1 family……………………...……………….18
1.3.2. Histone modifications………………………………………..…….…19
1.3.2.1. Acetylation ……………………………………..………………20
1.3.2.1.1. MYST family………………………………..……….……21
1.3.2.1.1.1. MOF…………………………………………………22
1.3.2.2. Deacetylation……………………………………………………22
1.3.2.3. Phosphorylation………………………………………...………23
1.3.2.4. Methylation……………………………………………….…….24
1.3.2.5. Deimination……………………………………………………..26
1.3.2.6. Ubiquitylation, deubiquitylation and sumoylation………..…27
1.4. Dosage compensation as a model of chromatin regulation of gene
expression……………………………………………………………………………28
291.4.1. Evolution of dosage compensation………………………………..28
1.4.2. Dosage compensation in birds………………………………….……30
1.4.3. Dosage compensation in Caenorhabditis elegans……….………..…31
1.4.4. Dosage compensation in mammals………………………….………33
1.4.5. Dosage compensation in Drosophila………………………………...35
1.4.6. Mechanism of dosage compensation……………………..………….39
1.4.6.1. Choosing the sex……………………………………………..…39
1.4.6.2. Targeting the X …………………………………………...……40
2. AIMS AND OBJECTIVES………………………………………………………43
2