Department of Radiation Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
Int J Mol Sci. 2016 Feb 27;17(3):310. doi: 10.3390/ijms17030310.
Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and also aging. Cells have evolved elaborate mechanisms to deal with DNA damage. Networks of DNA damage response (DDR) pathways are coordinated to detect and repair DNA damage, regulate cell cycle and transcription, and determine the cell fate. Upstream factors of DNA damage checkpoints and repair, "sensor" proteins, detect DNA damage and send the signals to downstream factors in order to maintain genomic integrity. Unexpectedly, we have discovered that an RNA-processing factor is involved in DNA repair processes. We have identified a gene that contributes to glioblastoma multiforme (GBM)'s treatment resistance and recurrence. This gene, RBM14, is known to function in transcription and RNA splicing. RBM14 is also required for maintaining the stem-like state of GBM spheres, and it controls the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway by interacting with KU80. RBM14 is a RNA-binding protein (RBP) with low complexity domains, called intrinsically disordered proteins (IDPs), and it also physically interacts with PARP1. Furthermore, RBM14 is recruited to DNA double-strand breaks (DSBs) in a poly(ADP-ribose) (PAR)-dependent manner (unpublished data). DNA-dependent PARP1 (poly-(ADP) ribose polymerase 1) makes key contributions in the DNA damage response (DDR) network. RBM14 therefore plays an important role in a PARP-dependent DSB repair process. Most recently, it was shown that the other RBPs with intrinsically disordered domains are recruited to DNA damage sites in a PAR-dependent manner, and that these RBPs form liquid compartments (also known as "liquid-demixing"). Among the PAR-associated IDPs are FUS/TLS (fused in sarcoma/translocated in sarcoma), EWS (Ewing sarcoma), TARF15 (TATA box-binding protein-associated factor 68 kDa) (also called FET proteins), a number of heterogeneous nuclear ribonucleoproteins (hnRNPs), and RBM14. Importantly, various point mutations within the FET genes have been implicated in pathological protein aggregation in neurodegenerative diseases, specifically with amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration (FTLD). The FET proteins also frequently exhibit gene translocation in human cancers, and emerging evidence shows their physical interactions with DDR proteins and thus implies their involvement in the maintenance of genome stability.
活细胞会因复制错误和氧化代谢、暴露于环境因子（如紫外线、电离辐射（IR））以及癌症治疗的放射疗法和化疗）而经历 DNA 损伤。DNA 损伤的积累会导致多种疾病，如神经退行性疾病、癌症、免疫缺陷、不孕以及衰老。细胞已经进化出精细的机制来处理 DNA 损伤。DNA 损伤反应（DDR）途径网络协同作用以检测和修复 DNA 损伤、调节细胞周期和转录，并决定细胞命运。DNA 损伤检查点和修复的上游因素，“传感器”蛋白，检测 DNA 损伤并将信号发送到下游因素，以维持基因组完整性。出乎意料的是，我们发现一种 RNA 加工因子参与了 DNA 修复过程。我们已经确定了一个导致胶质母细胞瘤（GBM）耐药和复发的基因。该基因 RBM14 已知在转录和 RNA 剪接中发挥作用。RBM14 对于维持 GBM 球体的干细胞样状态也是必需的，并且它通过与 KU80 相互作用来控制 DNA-PK 依赖性非同源末端连接（NHEJ）途径。RBM14 是一种 RNA 结合蛋白（RBP），具有低复杂度结构域，称为无序蛋白（IDP），它还与 PARP1 发生物理相互作用。此外，RBM14 以依赖多聚（ADP-核糖）（PAR）的方式被募集到 DNA 双链断裂（DSB）（未发表的数据）。DNA 依赖性 PARP1（多聚（ADP）核糖聚合酶 1）在 DNA 损伤反应（DDR）网络中做出关键贡献。因此，RBM14 在依赖 PARP 的 DSB 修复过程中发挥重要作用。最近，已经表明具有无序结构域的其他 RBPs 以依赖 PAR 的方式被募集到 DNA 损伤部位，并且这些 RBPs 形成液体隔室（也称为“液体分离”）。在 PAR 相关 IDP 中，有 FUS/TLS（肉瘤融合/肉瘤转移）、EWS（尤文肉瘤）、TARF15（TATA 框结合蛋白相关因子 68 kDa）（也称为 FET 蛋白）、许多异质核核糖核蛋白（hnRNPs）和 RBM14。重要的是，FET 基因中的各种点突变与神经退行性疾病中的病理性蛋白聚集有关，特别是肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）。FET 蛋白也经常在人类癌症中表现出基因易位，并且新出现的证据表明它们与 DDR 蛋白的物理相互作用，这意味着它们参与维持基因组稳定性。
