Cell Reports (May 2025)

Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes

  • Simona Pepe,
  • Federico Guerra,
  • Marco Russo,
  • Renée C. Duardo,
  • Giovanni Capranico

DOI
https://doi.org/10.1016/j.celrep.2025.115706
Journal volume & issue
Vol. 44, no. 5
p. 115706

Abstract

Read online

Summary: Guanine quadruplexes (G4s) are non-canonical DNA structures that can trigger micronuclei (MNi). Mechanisms of micronuclei formation by G4s are not fully understood. Here, we show that G4 stabilization can trigger cell-cycle-phase-specific mechanisms of replication fork stalling and DNA synthesis restart dependent on translesion synthesis (TLS) DNA polymerases (Pols). Fork stalling is caused by G-loops and high transcription during early S only. Moreover, while induction of micronuclei is dependent on DNA Pol η throughout S phase, primase and DNA-directed polymerase (PrimPol) is required in late S only. DNA breakage is not an immediate response to stabilized G4s but rather a consequence of persistent G4-mediated replication stress. Thus, different modes of fork stalling and restart, based on genomic context and TLS Pols, avoid immediate DNA breakage at stalled forks but at the expense of a risk of later mitotic chromosomal instability. The insights can lead to the development of more effective therapies for cancer and neurological diseases.

Keywords