Identifying inhibitors of the nuclear kinesin, KIF18B, and a new component of the DNA damage response TUBA4B

Various forms of endogenous and exogenous damage threatens the integrity of our DNA each day. To combat this cells have evolved various pathways to ensure the faithful repair of DNA after damage, the main two being non-homologous end joining (NHEJ) and homologous recombination (HR). The Lowndes group identified the nuclear kinesin, KIF18B, as a novel binding protein of the central NHEJ mediator p53 binding protein 1 (53BP1, (Luessing et al., 2021). KIF18B was shown to bind to 53BP1 via a novel tudor interacting motif (TIM) and enhance the binding of 53BP1 to sites of DNA damage. Efficient 53BP1-dependent NHEJ was shown to require both the TIM and the motor functions of KIF18B. Therefore, in silico modelling of KIF18B was used to develop a chemical method, by identifying a wild-type inhibitor, and a chemical-genetic method, using an analogue sensitive approach, to inhibit the KIF18B motor function. Inhibition of KIF18B, as opposed to genetic knockdown, provides greater temporal resolution for studying its role in the DDR. Given the requirement for KIF18B motor function in 53BP1-dependent NHEJ, we hypothesised that the role of KIF18B may be microtubule-dependent. To address this, we surveyed the tubulin superfamily to identify variant tubulins which may function in the DNA damage response.

Funder

Science Foundation Ireland

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (PhD Theses)