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RBM45 competes with HDAC1 for binding to FUS in response to DNA damage

DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sc...

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Detalles Bibliográficos
Autores principales: Gong, Juanjuan, Huang, Min, Wang, Fengli, Ma, Xiaolu, Liu, Hongmei, Tu, Yingfeng, Xing, Lingyu, Zhu, Xuefei, Zheng, Hui, Fang, Junjie, Li, Xiaoling, Wang, Qiaochu, Wang, Jiuqiang, Sun, Zhongshuai, Wang, Xi, Wang, Yun, Guo, Caixia, Tang, Tie-Shan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728411/
https://www.ncbi.nlm.nih.gov/pubmed/29140459
http://dx.doi.org/10.1093/nar/gkx1102
Descripción
Sumario:DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process. Here, we report that RBM45 can be recruited to laser microirradiation-induced DNA damage sites in a PAR- and FUS-dependent manner, but in a RNA-independent fashion. Depletion of RBM45 leads to abnormal DDR signaling and decreased efficiency in DNA double-stranded break repair. Interestingly, RBM45 is found to compete with histone deacetylase 1 (HDAC1) for binding to FUS, thereby regulating the recruitment of HDAC1 to DNA damage sites. A common familial ALS-associated FUS mutation (FUS-R521C) is revealed to prefer to cooperate with RBM45 than HDAC1. Our findings suggest that RBM45 is a key regulator in FUS-related DDR signaling whose dysfunction may contribute to the pathogenesis of ALS.