title: DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis.
abstract: Human DNA polymerase η (Pol η) is best known for its role in responding to UV irradiation-induced genome damage. We have recently observed that Pol η is also required for the stability of common fragile sites (CFSs), whose rearrangements are considered a driving force of oncogenesis. Here, we explored the molecular mechanisms underlying this newly identified role. We demonstrated that Pol η accumulated at CFSs upon partial replication stress and could efficiently replicate non-B DNA sequences within CFSs. Pol η deficiency led to persistence of checkpoint-blind under-replicated CFS regions in mitosis, detectable as FANCD2-associated chromosomal sites that were transmitted to daughter cells in 53BP1-shielded nuclear bodies. Expression of a catalytically inactive mutant of Pol η increased replication fork stalling and activated the replication checkpoint. These data are consistent with the requirement of Pol η-dependent DNA synthesis during S phase at replication forks stalled in CFS regions to suppress CFS instability by preventing checkpoint-blind under-replicated DNA in mitosis.
authors.affiliation: Equipe labellisée Ligue Contre le Cancer 2013, INSERM Unit 1037, ERL5294 Centre National de la Recherche Scientifique, Cancer Research Center of Toulouse, BP3028, CHU Purpan, 31024 Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bergoglio
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Boyer
authors.forename: Erin
authors.initials: E
authors.lastname: Walsh
authors.forename: Valeria
authors.initials: V
authors.lastname: Naim
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Legube
authors.forename: Marietta Y W T
authors.initials: MY
authors.lastname: Lee
authors.forename: Laurie
authors.initials: L
authors.lastname: Rey
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Eckert
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hoffmann
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D004261:DNA Replication; D059371:DNA, B-Form / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D059765:Homologous Recombination; D006801:Humans; D055029:Inverted Repeat Sequences; D008938:Mitosis; D011485:Protein Binding; D059807:S Phase Cell Cycle Checkpoints; D013312:Stress, Physiological; D000099270:Y-Family DNA Polymerases
chemical_list: D059371:DNA, B-Form; D004259:DNA-Directed DNA Polymerase; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases