From alpha to omega: uncovering determinants of DNA damage signalling and DNA repair at telomeres

Faithful repair of DNA damage is essential to the maintenance of genomic integrity. Failure to repair DNA damage in a timely and accurate manner causes genomic instability and predisposes cells to malignant transformation. Nonetheless, DNA repair mechanisms need to be suppressed in the context of telomeres, where unwarranted damage signalling and repair events could lead to cellular senescence and fusions of chromosomes. In this
thesis, through functional genetic screens and mechanistic delineations, we uncovered new factors that critically control DNA repair at deprotected telomeres by impacting the pivotal DDR signalling event of KAP1-S824 phosphorylation. To study DNA damage and repair at telomeres, the TRF2ts system is a recurring tool that constitutes the technical basis of this thesis. The TRF2ts system enables synchronous, temperature-controlled induction of telomere deprotection that is rapid and reversible. Exploiting the unique advantages of the TRF2ts system, we developed functional genetic
screens that revealed the novel functional involvements of UBE2D3, OTUD5 and WDCP in telomere DNA repair by regulating the phosphorylation of KAP1-S824 triggered by telomere deprotection.