Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death

Functional telomeresare protected from non-homologous end-joining(NHEJ) and homologous recombination(HR) DNA repairpathways. Replication is a critical periodfor telomeresbecause of the requirement for reconstitution of functional protected telomereconformations, a process that involves DNA repairproteins. Using knockdown of DNA-PKcsand Rad51expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomereaberrations induced by the G-quadruplexligand 360A during or after replication. HR contributed to specific chromatid-type aberrations ( telomerelosses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomerefusions as a direct consequence of G-quadruplexformation and/or stabilization induced by 360A on parental telomereG strands. NHEJ and HR activation at telomeresaltered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomerefusions were associated with altered metaphase- anaphasetransition and anaphasebridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomeretargeting by the G-quadruplexligand 360A, leading to cancer cell death.