title: Break-induced telomere synthesis underlies alternative telomere maintenance.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dilley
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Verma
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nam Woo
authors.initials: NW
authors.lastname: Cho
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Harrison D
authors.initials: HD
authors.lastname: Winters
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Wondisford
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.|Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004258:DNA Polymerase III / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051818:Replication Protein C / Q000378:metabolism; D017385:Sequence Homology; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis; D000099272:Replisomes
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D004258:DNA Polymerase III; D004259:DNA-Directed DNA Polymerase; D009097:Multienzyme Complexes; D018809:Proliferating Cell Nuclear Antigen; D051818:Replication Protein C; D000099272:Replisomes; C576324:ATM protein, human; C576597:ATR protein, human; C435720:POLD3 protein, human