Unraveling the mechanisms of DNA damage repair in heterochromatin

Samenvatting

Heterochromatin comprises around 30% of the human genome and densely packages repetitive sequences in a specialized DNA domain, making it especially vulnerable for erroneous DNA damage repair. Improper repair of double-strand-breaks (DSBs) in repetitive sequences due to recombination within the same heterochromatic region or between non-homologous chromosomes could produce aberrant chromosomes that are often found in cancer. Although much is known about the regulation of DSB-repair in euchromatin, detailed knowledge on heterochromatin DNA damage repair is lacking. The goal of this project is to characterize factors and mechanisms required for heterochromatin repair, and to use this knowledge to improve our understanding of the function of heterochromatin in ensuring genome stability. We plan to develop targeted single-DSB systems that will greatly facilitate investigating the dynamic responses of heterochromatic DNA to DNA damage. These studies will generate the first single DSB analysis in heterochromatic regions and will provide a platform to answer important questions such as: Which proteins are recruited to heterochromatic DSBs and when? Which repair-mechanisms are being used in heterochromatin and how are these regulated? As such, this experimental approach will advance our understanding of how heterochromatic repetitive sequences are repaired, providing important insights into mechanisms that safeguard genomic stability.

Kenmerken

Projectnummer

825.13.006

Hoofdaanvrager

Dr. A. Janssen

Verbonden aan

Universiteit Utrecht, Universitair Medisch Centrum Utrecht, Medische Oncologie

Uitvoerders

Dr. A. Janssen

Looptijd

01/06/2013 tot 30/06/2015