Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cell. 2014 May 8;157(4):869-81. 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.
脆性 X 综合征是一种常见的遗传性智力障碍，由脆性 X 智力低下蛋白 FMRP 的缺失引起。FMRP 主要存在于细胞质中，在那里它调节对突触功能很重要的蛋白质的翻译。我们确定 FMRP 是一种染色质结合蛋白，在 DNA 损伤反应 (DDR) 中发挥作用。具体来说，我们表明 FMRP 通过其串联的结构域在体外与染色质结合，并在体内与染色质结合。我们还证明 FMRP 以依赖于染色质结合的方式参与 DDR。已知 DDR 机制在配子发生等发育过程中发挥重要作用。我们表明 FMRP 占据减数分裂染色体，并调节小鼠精子发生过程中 DDR 机制的动态。这些发现表明核 FMRP 在染色质界面调节基因组稳定性，并可能影响配子发生和脆性 X 综合征的某些发育方面。
