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

Valérie Bergoglio, Anne Sophie Boyer, Erin Walsh, Valeria Naim, Gaëlle Legube, Marietta Y.W.T. Lee, Laurie Rey, Filippo Rosselli, Christophe Cazaux, Kristin A. Eckert, Jean Sébastien Hoffmann

Research output: Contribution to journalArticle

104 Scopus citations

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 with in 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 underreplicated DNA in mitosis.

Original languageEnglish (US)
Pages (from-to)395-408
Number of pages14
JournalJournal of Cell Biology
Volume201
Issue number3
DOIs
StatePublished - Apr 2013

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Bergoglio, V., Boyer, A. S., Walsh, E., Naim, V., Legube, G., Lee, M. Y. W. T., Rey, L., Rosselli, F., Cazaux, C., Eckert, K. A., & Hoffmann, J. S. (2013). DNA synthesis by pol η promotes fragile site stability by preventing under-replicated DNA in mitosis. Journal of Cell Biology, 201(3), 395-408. https://doi.org/10.1083/jcb.201207066