Grant: Project Grant

Our DNA is under constant assault from environmental and internal factors. Fortunately, our cells can repair damaged DNA thereby preventing human illnesses such as cancer and premature aging. DNA repair mechanisms are evolutionarily conserved, from yeast to human. In fact, owing to its ease of manipulation, studies conducted in yeast have revealed numerous of the key players and processes mediating human DNA repair. One of the major DNA repair mechanisms is called homologous recombination, in which damaged DNA is replaced by DNA sequences copied from another intact sequence elsewhere in the cell. Importantly, we had found that for yeast cells to repair damaged DNA by homologous recombination, the damaged DNA must be transiently targeted to DNA hospital-like structures called nuclear pore complexes. This transient targeting is dependent on a DNA ambulance-like motor protein complex called Kinesin-14, another ambulance-like motor protein whose identity remains illusive, and protein filaments called microtubules [Chung et al. Nature Commun. (2015)]. This is puzzling as microtubules are typically not located in the part of the cell that contains the DNA and is called the nucleus. Yet, a similar dependence of DNA repair on motor proteins and microtubules was then reported in mammals and shown to impact the efficacy of anti-cancer drugs [Lottersberger et al. Cell (2015)]. Here we pursue new data revealing the formation of street-like microtubule filaments inside the DNA-containing nucleus. Thus, we will take advantage of the power of yeast genetics to test if these DNA damage-induced intranuclear microtubules (DIMs) act like roads that are driven onto by ambulance-like motor proteins to transport damaged DNA to and away from hospital-like sites of DNA repair. Overall, we will decipher a highly sought-after DNA repair mechanism that is critical to human health and longevity.