Break-induced telomere synthesis underlies alternative telomere maintenance

• Published in: Nature (London) Vol. 539; no. 7627; pp. 54 - 58
• Main Authors: Dilley, Robert L., Verma, Priyanka, Cho, Nam Woo, Winters, Harrison D., Wondisford, Anne R., Greenberg, Roger A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2016; Nature Publishing Group
• Subjects: 631/337/103/560; 631/337/1427; 631/80/103/560; 692/699/67/1344; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Line, Tumor; Chromosomes; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Polymerase III - metabolism; DNA Repair; DNA Replication; DNA synthesis; DNA-Directed DNA Polymerase - metabolism; Genomes; Health aspects; Humanities and Social Sciences; Humans; multidisciplinary; Multienzyme Complexes - metabolism; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Proliferating Cell Nuclear Antigen - metabolism; Replication Protein C - metabolism; Science; Sequence Homology; Telomerase; Telomere - metabolism; Telomere Homeostasis; Telomeres; Yeast
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature20099

Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10–15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC–PCNA–Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance. Alternative lengthening of telomeres in cancer cells is initiated by a specialized replisome and noncanonical homologous recombination at damaged telomeres, culminating in the synthesis of long tracts of telomere DNA. Telomere maintenance in cancer cells One aspect of cancer cells that contributes to their expansion and persistence is their ability to maintain telomere length as they continually divide. And one mechanism of telomere lengthening that does not utilize telomerase—and is found in more than one in ten cancers—is termed alternative lengthening of telomeres (ALT). Roger Greenberg and colleagues show here that a specialized replisome is formed in ALT-positive cancer cells that is capable of synthesizing long tracts of DNA at the telomere, proceeding from a double-strand break. This process is independent of many canonical replication- and homology-dependent repair components.