.............................................................................................................................................. xiv Introduction ............................................................................................................................................ 1 1. Chromatin structure ........................................................................................................................ 1 2. Chromatin remodelling ................................................................................................................... 1 3. Transcription .................................................................................................................................. 2 3.1. The FACT complex is a major regulator of nucleosome dynamics ........................................... 3 4. DNA damage response ................................................................................................................... 4 4.1. DNA damage signalling ............................................................................................................ 4 4.2. p53 activation during the DNA damage repair .......................................................................... 5 5. Chromatin and cancer ..................................................................................................................... 6 5.1. Clear cell renal cell carcinoma ................................................................................................... 6 6. Aims of the study............................................................................................................................ 6 Results and Discussion ........................................................................................................................... 8 1. SETD2 role in transcription ............................................................................................................ 8 1.1. Downregulation of SETD2 affects RNAPII turnover at the transcription site ........................... 8 1.2. SETD2 prevents widespread intragenic transcription initiation ............................................... 10 1.3. SETD2 promotes FACT recruitment ....................................................................................... 12 2. SETD2 role in DNA damage response ......................................................................................... 13 2.1. ccRCC cell lines as an experimental model system to investigate the tumour suppressor role of SETD2 ............................................................................................................................................ 13 2.2. SETD2 is required for DNA damage repair ............................................................................. 14 2.3. SETD2 is required for ATM activation following DNA damage ............................................ 16 2.4. SETD2 is needed for proper DNA damage signalling ............................................................. 17 2.5. SETD2 regulates p53 activity during DNA damage repair ...................................................... 18 2.6. The role of SETD2 in DDR is independent from H3K36me3 ................................................. 19 Conclusion and Outlook ....................................................................................................................... 21