TDP-43 mutations link Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage.
TDP-43 mutations link Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage.
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DOI：
10.1371/journal.pgen.1009260
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发表时间：
2020-12
期刊：
影响因子：
4.5
通讯作者：
Aguilera A
中科院分区：
文献类型：
--
作者：
Giannini M;Bayona-Feliu A;Sproviero D;Barroso SI;Cereda C;Aguilera A
TDP-43是一种参与RNA加工的DNA和RNA结合蛋白，与异质核糖核蛋白（hnRNP）结构相似，其缺失使神经元对双链DNA断裂（DSB）敏感。肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其中97%的患者是与TDP-43蛋白病和从细胞核清除TDP-43的条件相关的家族性和散发性病例，但我们对该疾病的分子基础知之甚少。在用HeLa细胞的非神经元模型显示TDP-43耗尽增加R环和相关的基因组不稳定性之后，我们证明突变的TDP-43（A382 T）在来自ALS患者的转染的神经元SH-SY 5 Y和淋巴母细胞样细胞系（LCL）中的错误定位引起R环积累、R环依赖性增加的DSB和范可尼贫血修复中心。这些结果揭示了TDP-43在控制共转录R环和通过防止有害的R环积累来维持基因组完整性中的新作用。因此，我们的研究结果将TDP-43病理学与增加的R环和R环介导的DNA损伤联系起来，从而打开了TDP-43缺陷细胞中的R环调节可能有助于开发ALS疗法的可能性。肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis，ALS）是一种成年发病的进行性神经退行性疾病，由大脑皮层、脑干和脊髓中的上运动神经元和下运动神经元的选择性丧失引起。核TDP-43 RNA结合蛋白由ALS易感性的主要基因编码，其突变在3%的家族性和2%的散发性ALS病例中发现。由于其识别DNA和RNA的能力，TDP-43参与mRNA代谢的不同步骤和基因组完整性的几种机制。这一点，再加上R环或DNA-RNA杂合体是基因组不稳定性的常见来源，促使我们研究TDP-43缺陷是否在R环稳态中具有任何作用，可以解释先前描述的ALS细胞的DNA损伤反应缺陷。我们发现TDP-43在神经元和非神经元细胞以及患者细胞系中预防R环积累和相关基因组不稳定性方面发挥作用。因此，我们的研究开启了TDP-43缺陷细胞中的R环调节可能有助于开发ALS疗法的可能性。
TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. After showing with the non-neuronal model of HeLa cells that TDP-43 depletion increases R loops and associated genome instability, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, R loop-dependent increased DSBs and Fanconi Anemia repair centers. These results uncover a new role of TDP-43 in the control of co-transcriptional R loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies. Amyotrophic Lateral Sclerosis (ALS) is an adult onset, progressive neurodegenerative disease, caused by the selective loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. The nuclear TDP-43 RNA binding protein, is encoded by a major gene for ALS susceptibility whose mutations are found in 3% of familial and 2% of sporadic ALS cases. Thanks to its ability to recognize DNA and RNA, TDP-43 is involved in different steps of mRNA metabolism and in several mechanisms of genome integrity. This, together with the fact that R loops or DNA-RNA hybrids are a common source of genome instability, prompted us to investigate whether TDP-43 deficiency has any role in R loop homeostasis that could explain previously described DNA damage response defects of ALS cells. We show that TDP-43 plays a role in preventing R loop-accumulation and associated genome instability in neuronal and non-neuronal cells, as well as in patient cell lines. Thus, our study opens the possibility that R loop-modulation in TDP-43-defective cells might help develop ALS therapies.
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