Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Author:

Chakraborty Arijita,Jenjaroenpun Piroon,McCulley Andrew,Li Jing,El Hilali Sami,Haarer Brian,Hoffman Elizabeth A.,Belak Aimee,Thorland Audrey,Hehnly Heidi,Chen Chun-long,Kuznetsov Vladimir A.,Feng WenyiORCID

Abstract

ABSTRACTFragile X syndrome (FXS) is the most prevalent inherited intellectual disability caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene. The protein product of FMR1, FMRP, is known as a translational repressor whose nuclear function is not understood. Here we report that FMRP is a genome maintenance protein. We show that FX cells exhibit elevated level of chromosome breaks, both spontaneous and replication stress-induced. We demonstrate that FMRP is required for abating R-loop accumulation, thereby preventing chromosome breakage. Through mapping FMRP-bound chromatin loci in normal cells and correlating with FX-specific chromosome breaks, we identified novel FXS-susceptible genes. We show that FX cells have reduced expression of the uridine diphosphoglucuronosyl transferase 1 family enzymes, suggesting defective xenobiotics glucuronidation and consequential neurotoxicity in FXS.

Publisher

Cold Spring Harbor Laboratory

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