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

ABSTRACT: Human DNA polymerase ? (Pol ?) is best known for its role in responding to UV irradiation-induced genome damage. We have recently observed that Pol ? 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 ? accumulated at CFSs upon partial replication stress and could efficiently replicate non-B DNA sequences within CFSs. Pol ? 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 ? increased replication fork stalling and activated the replication checkpoint. These data are consistent with the requirement of Pol ?-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.

SUBMITTER: Bergoglio V 

PROVIDER: S-EPMC3639397 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature