A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response

• Published in: Cell Vol. 157; no. 4; pp. 869 - 881
• Main Authors: Alpatov, Roman, Lesch, Bluma J., Nakamoto-Kinoshita, Mika, Blanco, Andres, Chen, Shuzhen, Stützer, Alexandra, Armache, Karim J., Simon, Matthew D., Xu, Chao, Ali, Muzaffar, Murn, Jernej, Prisic, Sladjana, Kutateladze, Tatiana G., Vakoc, Christopher R., Min, Jinrong, Kingston, Robert E., Fischle, Wolfgang, Warren, Stephen T., Page, David C., Shi, Yang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2014
• Subjects: Animals; chromatin; Chromatin - metabolism; Chromosome Pairing; cytoplasm; DNA Damage; Embryo, Mammalian - cytology; Fibroblasts; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Hippocampus - cytology; Histones - metabolism; Humans; Male; Meiosis; Mice; Mice, Knockout; Mutation; Neurons - metabolism; Prophase; Receptors, AMPA - metabolism; Spermatogenesis
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2014.03.040

Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome. [Display omitted] •Fragile X mental retardation protein FMRP binds chromatin via its Agenet domain•FMRP participates in the DNA damage response in a chromatin-dependent manner•FMRP occupies chromosomes and regulates DNA damage machinery in male mouse meiosis•Lack of FMRP results in meiotic defects such as incomplete chromosome pairing In addition to its classical role as a translational regulator at neuronal synapses, the fragile X mental retardation protein has a role in the nucleus, where it targets chromatin and regulates the DNA damage response and mammalian gametogenesis.