TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.
TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.
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DOI：
10.1038/s41467-023-40695-y
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发表时间：
2023-08-21
影响因子：
16.6
通讯作者：
Gambus, Agnieszka
中科院分区：
文献类型：
--
作者：
Scaramuzza, Shaun;Jones, Rebecca M. M.;Sadurni, Martina Muste;Reynolds-Winczura, Alicja;Poovathumkadavil, Divyasree;Farrell, Abigail;Natsume, Toyoaki;Rojas, Patricia;Cuesta, Cyntia Fernandez;Kanemaki, Masato T. T.;Saponaro, Marco;Gambus, Agnieszka
细胞分裂是生命繁衍的基础，需要准确复制所有遗传信息。复制过程中产生的 DNA 损伤（复制应激）是癌症、过早衰老和一系列其他人类疾病的主要原因。多年来，TRAIP E3 泛素连接酶已被证明在控制基因组完整性和完美分离的各种细胞过程中发挥作用。 TRAIP 对于细胞活力至关重要，TRAIP 泛素连接酶活性突变会导致患者出现原始侏儒症。在这里，我们确定了 TRAIP 耗尽的细胞中抑制细胞增殖的机制。我们利用生长素诱导的降解决定子系统快速降解细胞内的TRAIP，并剖析TRAIP在细胞周期不同阶段的各种功能的重要性。我们得出的结论是，在 TRAIP 快速降解时，特别是在 S 期，细胞停止增殖，停滞在细胞周期的 G2 阶段并经历衰老。我们的研究结果表明，TRAIP 在 S 期发挥作用，防止复制-转录冲突引起的转录起始位点 DNA 损伤。 TRAIP E3 泛素连接酶对于基因组完整性至关重要，突变会导致患者出现原始侏儒症。在此，作者表明，S 期的 TRAIP 降解会因复制-转录冲突引起的 DNA 损伤而导致细胞停滞。
Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts. The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
4.8
作者：
Gillespie, Peter J.;Gambus, Agnieszka;Blow, J. Julian
通讯作者：
Blow, J. Julian
影响因子：
64.5
作者：
Duxin JP;Dewar JM;Yardimci H;Walter JC
通讯作者：
Walter JC
DOI：
10.1038/nrc.2017.52
发表时间：
2017-07-25
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Glover TW;Wilson TE;Arlt MF
通讯作者：
Arlt MF
影响因子：
16.6
作者：
Franz A;Pirson PA;Pilger D;Halder S;Achuthankutty D;Kashkar H;Ramadan K;Hoppe T
通讯作者：
Hoppe T