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Nucleoporins: the building blocks of the NPC

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Academic year: 2021

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TABLE OF CONTENTS

Acknowledgements ... 2

Abbreviations ... 7

I. Introduction ... 10

1. The nuclear pore complex ... 10

1.1. NPC architecture ... 10

1.2. Nucleoporins: the building blocks of the NPC ... 13

1.3. Roles for NPCs and nucleoporins ... 16

1.4. Nup98 ... 22

2. Leukaemia ... 31

2.1. Haematopoiesis ... 31

2.2. Leukaemia subtypes ... 34

2.3. Nup98-related Leukaemia ... 36

3. DNA double-strand break repair pathways ... 52

3.1. Non-Homologous End Joining ... 55

3.2. Homologous Recombination ... 55

3.3. Single-Strand Annealing ... 56

3.4. Alternative Non-Homologous End Joining / Mircohomology-Mediated Repair ... 57

3.5. Crosslink Repair (Fanconi Anaemia / BRCA pathway) ... 57

4. Compromised DSB Repair in Leukaemia ... 58

4.1. Altered Non-Homologous End Joining ... 59

4.2. Altered Alternative Non-Homologous End Joining ... 62

4.3. Altered Homologous Recombination ... 64

4.4. Altered Single-Strand Annealing ... 65

4.5. Alterations in Other Repair Pathways ... 65

4.6. Indirect Effects on DDR ... 65

II. Aim of the study ... 68

III. Results ... 69

1. The expression of Nup98 fusions does not induce DNA DSBs ... 69

2. DSB repair kinetics are not altered by Nup98 fusion proteins ... 69

3. Nup98 fusions affect non-homologous end joining ... 73

4. NHA9 does not affect homologous recombination ... 77

5. The FG-repeats of Nup98 and the homeodomain of HoxA9 are essential for the effect on NHEJ ... 79

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