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.

journal_name

Nature

journal_title

Nature

authors

Dilley RL,Verma P,Cho NW,Winters HD,Wondisford AR,Greenberg RA

doi

10.1038/nature20099

subject

Has Abstract

pub_date

2016-11-03 00:00:00

pages

54-58

issue

7627

eissn

0028-0836

issn

1476-4687

pii

nature20099

journal_volume

539

pub_type

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