Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency

PLoS Genetics
Anthony SanchezYounghoon Kee

Abstract

Common fragile sites (CFSs) are breakage-prone genomic loci, and are considered to be hotspots for genomic rearrangements frequently observed in cancers. Understanding the underlying mechanisms for CFS instability will lead to better insight on cancer etiology. Here we show that Polycomb group proteins BMI1 and RNF2 are suppressors of transcription-replication conflicts (TRCs) and CFS instability. Cells depleted of BMI1 or RNF2 showed slower replication forks and elevated fork stalling. These phenotypes are associated with increase occupancy of RNA Pol II (RNAPII) at CFSs, suggesting that the BMI1-RNF2 complex regulate RNAPII elongation at these fragile regions. Using proximity ligase assays, we showed that depleting BMI1 or RNF2 causes increased associations between RNAPII with EdU-labeled nascent forks and replisomes, suggesting increased TRC incidences. Increased occupancy of a fork protective factor FANCD2 and R-loop resolvase RNH1 at CFSs are observed in RNF2 CRISPR-KO cells, which are consistent with increased transcription-associated replication stress in RNF2-deficient cells. Depleting FANCD2 or FANCI proteins further increased genomic instability and cell death of the RNF2-deficient cells, suggesting that in the absenc...Continue Reading

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Citations

Nov 20, 2020·Nature Reviews. Molecular Cell Biology·Melvin Noe GonzalezJesper Q Svejstrup
Apr 8, 2021·PLoS Genetics·Shuhe TsaiPeter C Stirling
May 31, 2021·Trends in Cancer·Akhil BowryEva Petermann
Jun 20, 2021·Journal of Biomedical Science·Chia-Ling HsuCheng-Fu Kao
Aug 28, 2021·Biomolecules·Commodore St GermainJacqueline H Barlow

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
ChIP
DNA
Assay
PCR
deubiquitination
PLA
scraping
crosslink-IP

Software Mentioned

BD Accuri C6
ImageJ
Volocity
Gen5

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