4.8 Article

EXO1 resection at G-quadruplex structures facilitates resolution and replication

Journal

NUCLEIC ACIDS RESEARCH
Volume 48, Issue 9, Pages 4960-4975

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa199

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Funding

  1. National Institute of General Medical Sciences [GM088351]
  2. National Cancer Institute [CA190492]
  3. NIH [GM074917]
  4. NSF [MCB 1818293]

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G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.

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