DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression
DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression
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DOI：
10.1073/pnas.1605828113
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发表时间：
2016-07-26
影响因子：
11.1
通讯作者：
Wiesmueller, Lisa
中科院分区：
文献类型：
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作者：
Hamppa, Stephanie;Kiesslinga, Tina;Wiesmueller, Lisa
DNA损伤耐受性促进了在模板链上遇到障碍的复制叉子的进展。它涉及由增殖细胞核抗原单素化启动的跨损伤DNA合成，或者较少被很好描述的分叉逆转和模板切换机制。在这里，我们描述了一种新的耐受途径，需要肿瘤抑制因子P53、跨损伤聚合酶IOTA(POL IOTA)、泛素连接酶RAD5相关的解旋酶样转录因子(HLTF)和SWI/SNF催化亚单位(SNF2)转位酶锌指结合结构域3(ZRANB3)。这种新的p53活性在核酸外切酶缺陷但转录活性的p53(H115N)突变体中丢失。野生型P53，而不是P53(H115N)，在体内与POL IOTA相关。值得注意的是，在未受干扰的DNA复制过程中，P53和POLIOTA的协同作用减缓了新生DNA的伸长，并促进了依赖于HLTF/ZRANB3的重组。尤其是在交联剂诱导的复制胁迫后，P53和POL IOTA还共同促进依赖于减数分裂重组酶11(Mre11)的(磷酸)复制蛋白A(RPA)包被的单链DNA的积累。这些结果暗示了P53在复制叉子的处理中的直接作用，该复制叉子在模板链上遇到障碍。我们的发现定义了P53和POLIOTA在内源性或外源性复制应激的DNA损伤反应中的前所未有的功能。
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.