Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Legorreta Cancer Center, Brown University, Providence, Rhode Island, USA.
Environ Mol Mutagen. 2024 Nov;65(9):315-337. doi: 10.1002/em.22623. Epub 2024 Sep 2.
ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.
ADP-核糖基化是一种可逆的翻译后修饰，在各种细胞过程中作为信号机制发挥作用。这种修饰的特点是结构多样性、高度动态性和半衰期短。因此，它在多个层面受到细胞因子的严格调控，这些因子可以精细调节其形成、下游信号转导和降解，从而共同影响细胞的结果。多聚 ADP-核糖基化是 DNA 损伤反应中的一种重要信号机制，通过其多聚 ADP-核糖（PAR）结合结构域（PBD）介导 DNA 修复因子在 DNA 损伤部位的募集。PAR 读取器，编码 PBD，传递 PAR 信号以介导细胞结果，在某些情况下，PAR 结构多样性可以决定这些结果。已经确定了几个 PBD 家族，每个家族的 PAR 结合亲和力和特异性都不同，它们还可以识别和结合 PAR 链的不同部分。PAR 化信号已成为治疗特定癌症类型的有吸引力的靶点，因为抑制 PAR 的形成或降解可以选择性地消除具有特定 DNA 修复缺陷的癌细胞，并增强放射或化学疗法的反应。在这篇综述中，我们总结了多聚 ADP-核糖基化及其调控的关键因素，并强调了 PBD 作为研究 PAR 化动力学的工具，以及在癌症治疗中靶向 PAR 化信号的扩展潜力。
