Break induced telomere synthesis underlies alternative telomere maintenance
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 d (Pol d) through its POLD3 subunit. Break induced telomere synthesis requires the RFC PCNA Pol d 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.
Nature