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

Chakraborty, A.; Jenjaroenpun, P.; McCulley, A.; Li, J.; El Hilali, S.; Haarer, B.; Hoffman, E. A.; Belak, A.; Thorland, A.; Hehnly, H.; Chen, C.-l.; Kuznetsov, V.; Feng, W.

doi:10.1101/601906

bioRxiv · 10.1101/601906

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

Chakraborty, A.·Jenjaroenpun, P.·McCulley, A.·Li, J.·El Hilali, S.·Haarer, B.·Hoffman, E. A.·Belak, A.·Thorland, A.·Hehnly, H.·Chen, C.-l.·Kuznetsov, V.·Feng, W.

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Abstract

Fragile 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.

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Chakraborty, A., Jenjaroenpun, P., McCulley, A., Li, J., El Hilali, S., Haarer, B., Hoffman, E. A., Belak, A., Thorland, A., Hehnly, H., Chen, C.-l., Kuznetsov, V., Feng, W.. 2019-04-08. Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility. https://doi.org/10.1101/601906

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