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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >DNA damage tolerance pathway involving DNA polymerase iota and the tumor suppressor p53 regulates DNA replication fork progression
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DNA damage tolerance pathway involving DNA polymerase iota and the tumor suppressor p53 regulates DNA replication fork progression

机译：DNA damage tolerance pathway involving DNA polymerase iota and the tumor suppressor p53 regulates DNA replication fork progression

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摘要

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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