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首页> 外文期刊>Nature cell biology >Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass
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Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass

机译：全系统泛素化动力学分析揭示了PAF15泛素化在DNA损伤旁路中的关键作用

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摘要

Protein ubiquitylation has emerged as a key regulatory mechanism in DNA-damage signalling and repair pathways. We report a proteome-wide, site-specific survey of ubiquitylation changes after ultraviolet irradiation, identifying numerous upregulated and downregulated ubiquitylation sites on known components of DNA-damage signalling, as well as on proteins not previously implicated in this process. Our results uncover a critical role for PCNA-associated factor PAF15 (p15(PAF)/KIAA0101) ubiquitylation during DNA replication. During unperturbed S phase, chromatin-associated PAF15 is modified by double mono-ubiquitylation of Lys 15 and 24 templated through PCNA binding. Replication blocks trigger rapid, proteasome-dependent removal of Lys 15/24-ubiquitylated PAF15 from PCNA, facilitating bypass of replication-fork- blocking lesions by allowing recruitment of translesion DNA synthesis polymerase polη to mono-ubiquitylated PCNA at stalled replisomes. Our findings demonstrate widespread involvement of ubiquitin signalling in genotoxic-stress responses and identify a critical function for dynamic PAF15 ubiquitylation in safeguarding genome integrity when DNA replication is challenged.
机译：蛋白质泛素化已成为DNA损伤信号转导和修复途径中的关键调控机制。我们报告了紫外线照射后泛素化变化的蛋白质组范围的，特定于位点的调查，确定了DNA损伤信号的已知成分以及先前未参与此过程的蛋白质上的许多上调和下调的泛素化位点。我们的结果揭示了DNA复制过程中PCNA相关因子PAF15（p15（PAF）/ KIAA0101）泛素化的关键作用。在不受干扰的S期，通过PCNA结合使模板化的Lys 15和24发生双单泛素化，从而修饰了染色质相关的PAF15。复制阻滞触发从PCNA迅速，蛋白酶体依赖性地去除Lys 15 / 24-泛素化的PAF15，通过允许在停滞的复制子处将跨病变的DNA合成聚合酶pol募集到单泛素化的PCNA，从而促进绕过复制叉的病变。我们的发现表明泛素信号传导广泛参与了遗传毒性应激反应，并在DNA复制受到挑战时确定了动态PAF15泛素化在保护基因组完整性中的关键功能。

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