Bou Samra Elias, Buhagiar-Labarchède Géraldine, Machon Christelle, Guitton Jérôme, Onclercq-Delic Rosine, Green Michael R, Alibert Olivier, Gazin Claude, Veaute Xavier, Amor-Guéret Mounira
Institut Curie, PSL Research University, UMR 3348, Orsay, 91405, France.
CNRS UMR 3348, Centre Universitaire, Orsay, 91405, France.
Nat Commun. 2017 Sep 25;8(1):693. doi: 10.1038/s41467-017-00633-1.
Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis, ribonucleotide levels, and affects ribosomal DNA stability, leading to the formation of a new subclass of human ribosomal ultrafine anaphase bridges. We describe here Tau functions in maintaining survival of cytidine deaminase-deficient cells, and ribosomal DNA transcription and stability. Moreover, our findings for cancer tissues presenting concomitant cytidine deaminase underexpression and Tau upregulation open up new possibilities for anti-cancer treatment.Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability.
布卢姆综合征患者的细胞由于BLM缺陷和胞苷脱氨酶下调而表现出基因组不稳定。在此,我们使用全基因组RNA干扰合成致死筛选和转录组分析来鉴定使BLM缺陷和/或胞苷脱氨酶缺陷细胞能够耐受持续性DNA损伤和复制应激的基因。我们发现胞苷脱氨酶和微管相关蛋白Tau缺陷之间存在合成致死相互作用。Tau在胞苷脱氨酶缺陷细胞中过表达,其缺失会加剧基因组不稳定,损害细胞存活。Tau与上游结合因子一起被招募到核糖体DNA位点。Tau下调会减少上游结合因子的招募、核糖体RNA合成、核糖核苷酸水平,并影响核糖体DNA稳定性,导致形成一种新的人类核糖体超微后期桥子类。我们在此描述了Tau在维持胞苷脱氨酶缺陷细胞存活以及核糖体DNA转录和稳定性方面的功能。此外,我们对同时存在胞苷脱氨酶低表达和Tau上调的癌组织的研究结果为抗癌治疗开辟了新的可能性。胞苷脱氨酶(CDA)缺陷导致基因组不稳定。作者在此发现CDA与微管相关蛋白Tau缺陷之间存在合成致死相互作用,并报告Tau缺失会影响rRNA合成、核糖核苷酸库平衡和rDNA稳定性。