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NEAT1调节TIRR/53BP1复合体,以保持基因组的完整性

Susan Kilgas¹, Aleem Syed¹, Patrick Toolan-Kerr^2,3

¹Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Nature communications

|September 30, 2024

概括

图多互动修复调节器 (TIRR) 蛋白与NEAT1RNA结合,释放53BP1以修复DNA双链断裂 (DSB). 这种RNA结合相互作用依赖于细胞周期,并受到TDP-43.3的影响.

科学领域:

分子生物学分子生物学
遗传学是一个遗传学.
细胞生物学细胞生物学

背景情况:

图多互动修复调节剂 (TIRR) 是一种RNA结合蛋白 (RBP),它抑制了53BP1进入DNA双链断裂 (DSB) 的途径.
了解DNA修复途径的调节机制对于疾病研究至关重要.

研究的目的:

为了识别直接与TIRR结合的RNA分子.
阐明NEAT1在调节TIRR/53BP1相互作用和DNA修复中的作用.
调查TDP-43对这种途径的影响.

主要方法:

单个核酸分辨率交叉链接接接着免疫沉 (iCLIP) 来识别与TIRR结合的RNA.
分析RNA结合动机和蛋白质复合物的相互作用.
细胞周期同步和分析.

主要成果:

长非编码RNA NEAT1,特别是它的短异型NEAT1_1,被确定为TIRR的主要RNA合作伙伴.
TIRR与NEAT1_1的高亲缘关系结合是由G丰富的基因介导的.
NEAT1_1结合会破坏TIRR/53BP1复合物的稳定,促进53BP1在DNA修复中的功能.
在G1阶段,NEAT1_1表达得到丰富,使得TIRR的抑制功能依赖于细胞周期.
TDP-43促进了NEAT1_1的产生,从而调节了TIRR/53BP1复合体.

结论:

NEAT1_1通过调节TIRR与53BP1的相互作用,作为DNA双链断裂修复的关键调节者.
通过NEAT1_1对53BP1功能进行细胞周期依赖的调节,对理解DNA修复忠实性有重大影响.
不调节NEAT1_1及其相互作用因素,包括TDP-43,可能导致各种疾病.

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