Kieffer Shaylee R, Lowndes Noel F
Centre for Chromosome Biology (CCB), Biomedical Sciences Building (BSB), School of Biological and Chemical Sciences, National University of Ireland, Galway (NUIG), Galway, Ireland.
Front Genet. 2022 Jan 31;13:793884. doi: 10.3389/fgene.2022.793884. eCollection 2022.
Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular responses to DSBs encompass a range of highly coordinated events designed to detect and respond appropriately to the damage, thereby preserving genomic integrity. In analogy with events occurring during viral infection, we appropriate the terms Immediate-Early, Early, and Late to describe the pre-repair responses to DSBs. A distinguishing feature of the Immediate-Early response is that the large protein condensates that form during the Early and Late response and are resolved upon repair, termed foci, are not visible. The Immediate-Early response encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, and MRN, as well as rapid repair by so-called 'fast-kinetic' canonical non-homologous end joining (cNHEJ). Initial binding of PARPs and the KU70/80 complex to breaks appears to be mutually exclusive at easily ligatable DSBs that are repaired efficiently by fast-kinetic cNHEJ; a process that is PARP-, ATM-, 53BP1-, Artemis-, and resection-independent. However, at more complex breaks requiring processing, the Immediate-Early response involving PARPs and the ensuing highly dynamic PARylation (polyADP ribosylation) of many substrates may aid recruitment of both KU70/80 and MRN to DSBs. Complex DSBs rely upon the Early response, largely defined by ATM-dependent focal recruitment of many signalling molecules into large condensates, and regulated by complex chromatin dynamics. Finally, the Late response integrates information from cell cycle phase, chromatin context, and type of DSB to determine appropriate pathway choice. Critical to pathway choice is the recruitment of p53 binding protein 1 (53BP1) and breast cancer associated 1 (BRCA1). However, additional factors recruited throughout the DSB response also impact upon pathway choice, although these remain to be fully characterised. The Late response somehow channels DSBs into the appropriate high-fidelity repair pathway, typically either 'slow-kinetic' cNHEJ or homologous recombination (HR). Loss of specific components of the DSB repair machinery results in cells utilising remaining factors to effect repair, but often at the cost of increased mutagenesis. Here we discuss the complex regulation of the Immediate-Early, Early, and Late responses to DSBs proceeding repair itself.
遗传信息的丢失或重排可能源于对DNA双链断裂（DSB）的错误反应。细胞对DSB的反应包括一系列高度协调的事件，旨在检测并对损伤做出适当反应，从而维护基因组完整性。类比病毒感染期间发生的事件，我们采用即时早期、早期和晚期这些术语来描述对DSB的修复前反应。即时早期反应的一个显著特征是，在早期和晚期反应期间形成并在修复时解体的大型蛋白质凝聚物（称为病灶）不可见。即时早期反应包括初始损伤感知，涉及多聚（ADP - 核糖）聚合酶（PARP）、KU70/80和MRN，以及通过所谓的“快速动力学”经典非同源末端连接（cNHEJ）进行的快速修复。在通过快速动力学cNHEJ有效修复的易于连接的DSB处，PARP和KU70/80复合物与断裂处的初始结合似乎相互排斥；这是一个不依赖PARP、ATM（共济失调毛细血管扩张症突变基因）、53BP1（p53结合蛋白1）、Artemis（一种核酸酶）和切除的过程。然而，在需要处理的更复杂断裂处，涉及PARP的即时早期反应以及随之而来的许多底物的高度动态PAR化（多聚ADP核糖基化）可能有助于将KU70/80和MRN募集到DSB处。复杂的DSB依赖于早期反应，这主要由ATM依赖的许多信号分子向大型凝聚物的病灶募集所定义，并受复杂的染色质动力学调节。最后，晚期反应整合来自细胞周期阶段、染色质背景和DSB类型的信息，以确定合适的途径选择。途径选择的关键是p53结合蛋白1（53BP1）和乳腺癌相关蛋白1（BRCA1）的募集。然而，在整个DSB反应过程中募集的其他因素也会影响途径选择，尽管这些因素仍有待充分表征。晚期反应以某种方式将DSB引导至合适的高保真修复途径，通常是“慢速动力学”cNHEJ或同源重组（HR）。DSB修复机制特定成分的缺失会导致细胞利用剩余因子进行修复，但往往以增加诱变率为代价。在这里，我们讨论在修复本身之前对DSB的即时早期、早期和晚期反应的复杂调控。
