DNA Damage Promotes Microtubule Dynamics Through A DNA-PK-AKT Axis For Enhanced Repair

The instability of the genome is closely associated with developmental defects,premature aging,chronic diseases,cancer,and decreased anti-infective capacity.Therefore,ensuring the stability of the genome is an important aspect of human health.Various disadvantages in organisms or the external environment result in different DNA damages such as DNA double or single-strand breaks,bases damage which lead to genome instability.The precise and efficient repair of DNA breaks plays a critical role in the maintenance of the stability of the genome.DNA double-strand breaks(DSBs)are the most deleterious form of DNA damages in living organisms.To counteract the deleterious effects,here are two major repair pathways,canonical nonhomologous end joining(c-NHEJ)and homologous recombination(HR).When DNA double-strand breaks occur,the mobility of DSBs and chromatin surrounding DSBs increased,which ensures the quickly reconnection of two fractured ends.Therefore,the high mobility of DSBs plays a critical role in the rapid and efficient repair of DSBs.Although microtubule dynamics have been shown to regulate DSB mobility,the reverse effect of DSBs on microtubule dynamics remains elusive.Here,we uncovered a novel DSB-induced microtubule dynamics stress response named DMSR.In DMSR,DSBs can induce interphase centrosome maturation and enhance centrosome-dependent microtubule nucleation and elongation,which promotes DSBs mobility and facilitates c-NHEJ repair.DSBs led to the recruitment of pericentriolar material(PCM)on the interphase centrosome,especially PCNT(Pericentrin),?-tubulin,and NEDD1.With the recruitment of PCM,which is hallmarks of centrosome maturation,centrosome-dependent microtubule nucleation and elongation is increased.Intriguingly,DSBs-induced interphase centrosome maturation occurs during interphase and depends on DNA-PK-AKT axis but not classic mitotic kinase-PLK1.Depletion of centrosome proteins attenuates DMSR and the mobility of DSBs,resulting in delayed c-NHEJ.Remarkably,DMSR occurs only in G1 or G0 phase cells and lasts around 6h.Both inhibitions of DNA-PK and 53BP1 abolish DMSR.Taken together,our study reveals a novel mechanism,which positively regulates DNA damage repair in G1 or G0 phase cells through promoting microtubule dynamics and facilitating the c-NHEJ process.