Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, East Sussex BN19RQ, UK.
DNA Repair (Amst). 2020 Sep;93:102915. doi: 10.1016/j.dnarep.2020.102915.
In mammalian cells, the mediator protein, 53BP1, exerts distinct impacts on the repair of DNA double strand breaks (DSBs) depending on the setting, for example whether the DSBs arise at telomeres or during replication or class switch recombination. Here, we focus on two roles of 53BP1 in response to ionising radiation (IR)-induced DSBs (IR-DSBs). Canonical DNA non-homologous end-joining (c-NHEJ) is the major DSB repair pathway with homologous recombination (HR) contributing to DSB repair in S/G2 phase. ATM signalling promotes histone modifications and protein assembly in the DSB vicinity, which can be visualised as irradiation induced foci (IRIF). 53BP1 assembles at DSBs in a complex manner involving the formation of nano-domains. In G1 and G2 phase, X- or gamma-ray induced DSBs are repaired with biphasic kinetics. 70-80 % of DSBs are repaired with fast kinetics in both cell cycle phases by c-NHEJ; the remaining DSBs are repaired with slower kinetics in G2 phase via HR and in G1 by a specialised form of c-NHEJ termed Artemis and resection-dependent c-NHEJ, due to a specific requirement for the nuclease, Artemis and resection factors. 53BP1 is essential for the repair of DSBs rejoined with slow kinetics in G1 and G2 phase. This 53BP1 function requires its tandem BRCT domain and interaction with NBS1. As a distinct function, 53BP1 suppresses resection during both HR and Artemis and resection-dependent c-NHEJ. This latter role requires RIF1 and is counteracted by BRCA1. 53BP1 appears to be dispensable for the rejoining of the fast c-NHEJ repair process.
在哺乳动物细胞中，衔接蛋白 53BP1 根据不同的情况（例如，双链断裂 (DSB) 是否发生在端粒上或在复制或类别转换重组过程中）对 DNA 双链断裂 (DSB) 的修复产生明显的影响。在这里，我们主要关注 53BP1 在应对电离辐射 (IR) 诱导的 DSB (IR-DSB) 时的两个作用。经典的非同源末端连接 (c-NHEJ) 是主要的 DSB 修复途径，而同源重组 (HR) 在 S/G2 期有助于 DSB 修复。ATM 信号促进 DSB 附近的组蛋白修饰和蛋白质组装，这些可以被可视化成辐射诱导焦点 (IRIF)。53BP1 以涉及纳米域形成的复杂方式组装在 DSB 上。在 G1 和 G2 期，X 或 γ射线诱导的 DSB 以双相动力学修复。在两个细胞周期阶段，70-80%的 DSB 通过 c-NHEJ 以快速动力学修复；其余的 DSB 通过 G2 期的 HR 和 G1 期的一种特殊形式的 c-NHEJ 以较慢的动力学修复，这种特殊形式的 c-NHEJ 称为 Artemis 和依赖于切除的 c-NHEJ，这是由于对核酸内切酶、Artemis 和切除因子的特殊需求。53BP1 对于 G1 和 G2 期以慢动力学方式重新连接的 DSB 修复是必不可少的。这种 53BP1 功能需要其串联 BRCT 结构域和与 NBS1 的相互作用。作为一种独特的功能，53BP1 抑制 HR 和 Artemis 以及依赖于切除的 c-NHEJ 过程中的切除。后一种作用需要 RIF1，并且被 BRCA1 抵消。53BP1 似乎对于快速 c-NHEJ 修复过程的连接是可有可无的。
