Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 30, Pages E4311-E4319Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605828113
Keywords
DNA damage bypass; DNA polymerase idling; nascent DNA elongation; polymerase iota; p53
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Funding
- German Research Foundation (DFG) [1789, A3]
- Proyecto de investigacion cientifica y/o tecnologica (PICT) [2013-1049]
- DFG (Graduate School of Molecular Medicine, Ulm University) PhD fellowship
- State of Baden-Wurttemberg
- Dr. med scholarship for Experimental Medicine (Ulm University)
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DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase iota (POL iota), the ubiquitin ligase Rad5-related helicase-like transcription factor ( HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53( H115N), associates with POL iota in vivo. Strikingly, the concerted action of p53 and POL iota decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linkerinduced replication stress, p53 and POL iota also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POL iota in the DNA damage response to endogenous or exogenous replication stress.
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