Bibliographic Details
| Title: |
Replication Stress Induces Global Chromosome Breakage in the Fragile X Genome |
| Authors: |
Arijita Chakraborty, Piroon Jenjaroenpun, Jing Li, Sami El Hilali, Andrew McCulley, Brian Haarer, Elizabeth A. Hoffman, Aimee Belak, Audrey Thorland, Heidi Hehnly, Carl Schildkraut, Chun-long Chen, Vladimir A. Kuznetsov, Wenyi Feng |
| Source: |
Cell Reports, Vol 32, Iss 12, Pp 108179- (2020) |
| Publisher Information: |
Elsevier, 2020. |
| Publication Year: |
2020 |
| Collection: |
LCC:Biology (General) |
| Subject Terms: |
fragile X syndrome, FXS, FMRP, I304N, DNA double-strand breaks, DSB, Biology (General), QH301-705.5 |
| More Details: |
Summary: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene and deficiency of a functional FMRP protein. FMRP is known as a translation repressor whose nuclear function is not understood. We investigated the global impact on genome stability due to FMRP loss. Using Break-seq, we map spontaneous and replication stress-induced DNA double-strand breaks (DSBs) in an FXS patient-derived cell line. We report that the genomes of FXS cells are inherently unstable and accumulate twice as many DSBs as those from an unaffected control. We demonstrate that replication stress-induced DSBs in FXS cells colocalize with R-loop forming sequences. Exogenously expressed FMRP in FXS fibroblasts ameliorates DSB formation. FMRP, not the I304N mutant, abates R-loop-induced DSBs during programmed replication-transcription conflict. These results suggest that FMRP is a genome maintenance protein that prevents R-loop accumulation. Our study provides insights into the etiological basis for FXS. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2211-1247 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2211124720311682; https://doaj.org/toc/2211-1247 |
| DOI: |
10.1016/j.celrep.2020.108179 |
| Access URL: |
https://doaj.org/article/17e03ba499cf463582b53bebc5c45501 |
| Accession Number: |
edsdoj.17e03ba499cf463582b53bebc5c45501 |
| Database: |
Directory of Open Access Journals |
