Telomeric Double Strand Breaks in G1 Human Cells Facilitate Formation of 5? C-Rich Overhangs and Recruitment of TERRA

Telomeres, repetitive nucleoprotein complexes that protect chromosomal termini and prevent them from activating inappropriate DNA damage responses (DDRs), shorten with cell division thus aging. Here, we characterized the human cellular response to targeted telomeric double-strand breaks (DSBs) in telomerase-positive telomerase-independent alternative lengthening of telomere (ALT) cells, specifically G1 phase. Telomeric DSBs cells elicited early signatures a DDR; however, localization 53BP1, an important regulator resection at broken ends, was not observed break sites. Consistent this finding previously reported repression classical non-homologous end-joining (c-NHEJ) telomeres, evidence for c-NHEJ also lacking. Likewise, no homologous recombination (HR)-dependent repair observed. Rather, supportive rapid truncation events, facilitated formation extensive tracks resected 5? C-rich single-stranded (ss)DNA, proposed marker recombination-dependent ALT pathway. Indeed, induction resulted significant increases (ss)telomeric G1, which rather than RPA, bound by complementary RNA, TERRA, presumably these exposed ends so they persist into S/G2 telomerase-mediated or HR-dependent elongation, while circumventing conventional pathways. Results demonstrate remarkable adaptability have implications persistent normal G1/G0 (e.g., lymphocytes), as well therapeutically relevant targets improve treatment ALT-positive tumors.