R-loop and Its Functions at the Regulatory Interfaces Between Transcription and (epi)genome

Overview

Journal Biochim Biophys Acta Gene Regul Mech

Publisher Elsevier

Specialties Biochemistry
Biophysics
Genetics
Molecular Biology

Date 2021 Aug 30

PMID 34461314

Citations 17

Authors

Arum Kim

Gang Greg Wang

Affiliations

Soon will be listed here.

Abstract

R-loop represents a prevalent and specialized chromatin structure critically involved in a wide range of biological processes. In particular, co-transcriptional R-loops, produced often due to RNA polymerase pausing or RNA biogenesis malfunction, can initiate molecular events to context-dependently regulate local gene transcription and crosstalk with chromatin modifications. Cellular "readers" of R-loops are identified, exerting crucial impacts on R-loop homeostasis and gene regulation. Mounting evidence also supports R-loop deregulation as a frequent, sometimes initiating, event during the development of human pathologies, notably cancer and neurological disorder. The purpose of this review is to cover recent advances in understanding the fundamentals of R-loop biology, which have started to unveil complex interplays of R-loops with factors involved in various biological processes such as transcription, RNA processing and epitranscriptomic modification (such as N6-methyladenosine), DNA damage sensing and repair, and epigenetic regulation.

Citing Articles

Maf-family bZIP transcription factor NRL interacts with RNA-binding proteins and R-loops in retinal photoreceptors.

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Cross-regulation of RNA methylation modifications and R-loops: from molecular mechanisms to clinical implications.

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Maf-family bZIP transcription factor NRL interacts with RNA-binding proteins and R-loops in retinal photoreceptors.

Corso-Diaz X, Liang X, Preston K, Preston Jr K, Tegshee B, English M bioRxiv. 2024; .

PMID: 39345562 PMC: 11430021. DOI: 10.1101/2024.09.19.613899.

Epigenetic insights into Fragile X Syndrome.

Xie L, Li H, Xiao M, Chen N, Zang X, Liu Y Front Cell Dev Biol. 2024; 12:1432444.

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References

Tan-Wong S, Dhir S, Proudfoot N . R-Loops Promote Antisense Transcription across the Mammalian Genome. Mol Cell. 2019; 76(4):600-616.e6. PMC: 6868509. DOI: 10.1016/j.molcel.2019.10.002. View

Nguyen H, Leong W, Li W, Reddy P, Sullivan J, Walter M . Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes. Cancer Res. 2018; 78(18):5363-5374. PMC: 6139047. DOI: 10.1158/0008-5472.CAN-17-3970. 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

Konig F, Schubert T, Langst G . The monoclonal S9.6 antibody exhibits highly variable binding affinities towards different R-loop sequences. PLoS One. 2017; 12(6):e0178875. PMC: 5464589. DOI: 10.1371/journal.pone.0178875. View

Stolz R, Sulthana S, Hartono S, Malig M, Benham C, Chedin F . Interplay between DNA sequence and negative superhelicity drives R-loop structures. Proc Natl Acad Sci U S A. 2019; 116(13):6260-6269. PMC: 6442632. DOI: 10.1073/pnas.1819476116. 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

Zhou K, Pan T . An additional class of mA readers. Nat Cell Biol. 2018; 20(3):230-232. PMC: 5831501. DOI: 10.1038/s41556-018-0046-y. View

Lam F, Kong Y, Huang Q, Vu Han T, Maffa A, Kasper E . BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage. Nat Commun. 2020; 11(1):4083. PMC: 7428008. DOI: 10.1038/s41467-020-17503-y. View

Lee C, McNerney C, Ma K, Zhao W, Wang A, Myong S . R-loop induced G-quadruplex in non-template promotes transcription by successive R-loop formation. Nat Commun. 2020; 11(1):3392. PMC: 7341879. DOI: 10.1038/s41467-020-17176-7. View

10.

Pavri R . R Loops in the Regulation of Antibody Gene Diversification. Genes (Basel). 2017; 8(6). PMC: 5485518. DOI: 10.3390/genes8060154. View

11.

Leela J, Syeda A, Anupama K, Gowrishankar J . Rho-dependent transcription termination is essential to prevent excessive genome-wide R-loops in Escherichia coli. Proc Natl Acad Sci U S A. 2012; 110(1):258-63. PMC: 3538224. DOI: 10.1073/pnas.1213123110. View

12.

Xu W, Xu H, Li K, Fan Y, Liu Y, Yang X . The R-loop is a common chromatin feature of the Arabidopsis genome. Nat Plants. 2017; 3(9):704-714. DOI: 10.1038/s41477-017-0004-x. View

13.

DAlessandro G, Whelan D, Howard S, Vitelli V, Renaudin X, Adamowicz M . BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment. Nat Commun. 2018; 9(1):5376. PMC: 6299093. DOI: 10.1038/s41467-018-07799-2. View

14.

Nudler E . RNA polymerase backtracking in gene regulation and genome instability. Cell. 2012; 149(7):1438-45. PMC: 3815583. DOI: 10.1016/j.cell.2012.06.003. View

15.

Chen L, Chen J, Huang Y, Gu Y, Qiu J, Qian H . The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations. Mol Cell. 2018; 69(3):412-425.e6. PMC: 5957072. DOI: 10.1016/j.molcel.2017.12.029. View

16.

Roberts R, Crothers D . Stability and properties of double and triple helices: dramatic effects of RNA or DNA backbone composition. Science. 1992; 258(5087):1463-6. DOI: 10.1126/science.1279808. View

17.

Sollier J, Cimprich K . Breaking bad: R-loops and genome integrity. Trends Cell Biol. 2015; 25(9):514-22. PMC: 4554970. DOI: 10.1016/j.tcb.2015.05.003. View

18.

Yang X, Liu Q, Xu W, Zhang Y, Yang Y, Ju L . mA promotes R-loop formation to facilitate transcription termination. Cell Res. 2019; 29(12):1035-1038. PMC: 6951339. DOI: 10.1038/s41422-019-0235-7. View

19.

Cristini A, Groh M, Kristiansen M, Gromak N . RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage. Cell Rep. 2018; 23(6):1891-1905. PMC: 5976580. DOI: 10.1016/j.celrep.2018.04.025. View

20.

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