Cargando…

DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis

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 explor...

Descripción completa

Detalles Bibliográficos
Autores principales: Bergoglio, Valérie, Boyer, Anne-Sophie, Walsh, Erin, Naim, Valeria, Legube, Gaëlle, Lee, Marietta Y.W.T., Rey, Laurie, Rosselli, Filippo, Cazaux, Christophe, Eckert, Kristin A., Hoffmann, Jean-Sébastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639397/
https://www.ncbi.nlm.nih.gov/pubmed/23609533
http://dx.doi.org/10.1083/jcb.201207066
Descripción
Sumario: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.