DNA damage tolerance pathway involving DNA polymerase ? and the tumor suppressor p53 regulates DNA replication fork progression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 30; p. E4311
• Main Authors: Hampp, Stephanie, Kiessling, Tina, Buechle, Kerstin, Mansilla, Sabrina F, Thomale, Jürgen, Rall, Melanie, Ahn, Jinwoo, Pospiech, Helmut, Gottifredi, Vanesa, Wiesmüller, Lisa
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 26.07.2016
• Subjects: Binding sites; Cell division; DNA damage; Genes; Transcription factors; Tumors
• ISSN: 0027-8424; 1091-6490

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 ... (POL...), 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... in vivo. Strikingly, the concerted action of p53 and POL... decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POL... 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... in the DNA damage response to endogenous or exogenous replication stress. (ProQuest: ... denotes formulae/symbols omitted.)