The Chromatin Network Helps Prevent Cancer-associated Mutagenesis at Transcription-replication Conflicts

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 29

PMID 37898641

Authors

Aleix Bayona-Feliu

Emilia Herrera-Moyano

Nibal Badra-Fajardo

Ivan Galvan-Femenia

Maria Eugenia Soler-Oliva

Andres Aguilera

Affiliations

Soon will be listed here.

Abstract

Genome instability is a feature of cancer cells, transcription being an important source of DNA damage. This is in large part associated with R-loops, which hamper replication, especially at head-on transcription-replication conflicts (TRCs). Here we show that TRCs trigger a DNA Damage Response (DDR) involving the chromatin network to prevent genome instability. Depletion of the key chromatin factors INO80, SMARCA5 and MTA2 results in TRCs, fork stalling and R-loop-mediated DNA damage which mostly accumulates at S/G2, while histone H3 Ser10 phosphorylation, a mark of chromatin compaction, is enriched at TRCs. Strikingly, TRC regions show increased mutagenesis in cancer cells with signatures of homologous recombination deficiency, transcription-coupled nucleotide excision repair (TC-NER) and of the AID/APOBEC cytidine deaminases, being predominant at head-on collisions. Thus, our results support that the chromatin network prevents R-loops and TRCs from genomic instability and mutagenic signatures frequently associated with cancer.

Citing Articles

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References

Herrera-Moyano E, Mergui X, Garcia-Rubio M, Barroso S, Aguilera A . The yeast and human FACT chromatin-reorganizing complexes solve R-loop-mediated transcription-replication conflicts. Genes Dev. 2014; 28(7):735-48. PMC: 4015491. DOI: 10.1101/gad.234070.113. View

Tsai S, Fournier L, Chang E, Wells J, Minaker S, Zhu Y . ARID1A regulates R-loop associated DNA replication stress. PLoS Genet. 2021; 17(4):e1009238. PMC: 8055027. DOI: 10.1371/journal.pgen.1009238. View

Ortega P, Gomez-Gonzalez B, Aguilera A . Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion. Nat Commun. 2019; 10(1):5178. PMC: 6858524. DOI: 10.1038/s41467-019-13210-5. View

Bayona-Feliu A, Barroso S, Munoz S, Aguilera A . The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription-replication conflicts. Nat Genet. 2021; 53(7):1050-1063. DOI: 10.1038/s41588-021-00867-2. View

Zhang Y, Zhang D, Li Q, Liang J, Sun L, Yi X . Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat Genet. 2016; 48(9):1003-13. DOI: 10.1038/ng.3635. View

Rondinelli B, Gogola E, Yucel H, Duarte A, van de Ven M, van der Sluijs R . EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol. 2017; 19(11):1371-1378. DOI: 10.1038/ncb3626. View

Ginno P, Lott P, Christensen H, Korf I, Chedin F . R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol Cell. 2012; 45(6):814-25. PMC: 3319272. DOI: 10.1016/j.molcel.2012.01.017. View

Perez-Calero C, Bayona-Feliu A, Xue X, Barroso S, Munoz S, Gonzalez-Basallote V . UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide. Genes Dev. 2020; 34(13-14):898-912. PMC: 7328515. DOI: 10.1101/gad.336024.119. View

Bergstrom E, Huang M, Mahto U, Barnes M, Stratton M, Rozen S . SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genomics. 2019; 20(1):685. PMC: 6717374. DOI: 10.1186/s12864-019-6041-2. View

10.

Tate J, Bamford S, Jubb H, Sondka Z, Beare D, Bindal N . COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2018; 47(D1):D941-D947. PMC: 6323903. DOI: 10.1093/nar/gky1015. View

11.

Chen P, Chen H, Acharya D, Rando O, Fazzio T . R loops regulate promoter-proximal chromatin architecture and cellular differentiation. Nat Struct Mol Biol. 2015; 22(12):999-1007. PMC: 4677832. DOI: 10.1038/nsmb.3122. View

12.

Sessa G, Gomez-Gonzalez B, Silva S, Perez-Calero C, Beaurepere R, Barroso S . BRCA2 promotes DNA-RNA hybrid resolution by DDX5 helicase at DNA breaks to facilitate their repair‡. EMBO J. 2021; 40(7):e106018. PMC: 8013831. DOI: 10.15252/embj.2020106018. View

13.

Barroso S, Herrera-Moyano E, Munoz S, Garcia-Rubio M, Gomez-Gonzalez B, Aguilera A . The DNA damage response acts as a safeguard against harmful DNA-RNA hybrids of different origins. EMBO Rep. 2019; 20(9):e47250. PMC: 6726908. DOI: 10.15252/embr.201847250. View

14.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

15.

Kuhn R, Haussler D, Kent W . The UCSC genome browser and associated tools. Brief Bioinform. 2012; 14(2):144-61. PMC: 3603215. DOI: 10.1093/bib/bbs038. View

16.

Bhatia V, Barroso S, Garcia-Rubio M, Tumini E, Herrera-Moyano E, Aguilera A . BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature. 2014; 511(7509):362-5. DOI: 10.1038/nature13374. View

17.

Morgan M, Shilatifard A . Chromatin signatures of cancer. Genes Dev. 2015; 29(3):238-49. PMC: 4318141. DOI: 10.1101/gad.255182.114. View

18.

Neph S, Kuehn M, Reynolds A, Haugen E, Thurman R, Johnson A . BEDOPS: high-performance genomic feature operations. Bioinformatics. 2012; 28(14):1919-20. PMC: 3389768. DOI: 10.1093/bioinformatics/bts277. View

19.

Toh G, OShaughnessy A, Jimeno S, Dobbie I, Grenon M, Maffini S . Histone H2A phosphorylation and H3 methylation are required for a novel Rad9 DSB repair function following checkpoint activation. DNA Repair (Amst). 2006; 5(6):693-703. DOI: 10.1016/j.dnarep.2006.03.005. View

20.

Skourti-Stathaki K, Kamieniarz-Gdula K, Proudfoot N . R-loops induce repressive chromatin marks over mammalian gene terminators. Nature. 2014; 516(7531):436-9. PMC: 4272244. DOI: 10.1038/nature13787. View