Telomeric Recombination Induced by DNA Damage Results in Telomere Extension and Length Heterogeneity

Abstract

About 15% of human cancers counteract telomere loss by alternative lengthening of telomeres (ALT), which is attributed to homologous recombination (HR)–mediated events. But how telomeric HR leads to length elongation is poorly understood. Here, we explore telomere clustering and telomeric HR induced by double-stranded breaks (DSBs). We show that telomere clustering could occur at G1 and S phase of cell cycle and that three types of telomeric HR occur based on the manner of telomeric DNA exchange: equivalent telomeric sister chromatin exchange (T-SCE), inequivalent T-SCE, and No-SCE. While inequivalent T-SCE increases telomere length heterogeneity with no net gain of telomere length, No-SCE, which is presumably induced by interchromatid HR and/or break-induced replication, results in telomere elongation. Accordingly, cells subjected to long-term telomeric DSBs display increased heterogeneity of length and longer telomeres. We also demonstrate that DSBs-induced telomere elongation is telomerase independent. Moreover, telomeric recombination induced by DSBs is associated with formation of ALT-associated PML body and C-circle. Thus, DNA damage triggers recombination mediated elongation, leading to the induction of multiple ALT phenotypes.