Walking a tightrope: The complex balancing act of R-loops in genome stability

Brickner, Joshua R.; Garzon, Jada L.; Cimprich, Karlene A.

doi:10.1016/j.molcel.2022.04.014

Cited by 138 publications

(103 citation statements)

References 280 publications

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“…The MiDAS substrate is therefore a TRC-derived structure: either a fork stalled at an R-loop site or a DSB resulting from its collapse. Supporting the former possibility is our result that MiDAS occurs at R-loop sites enriched in G4s and highly transcribed, both leading to R-loop stabilization and fork stalling (Brickner et al, 2022). Supporting the latter is our result that ATM signaling is required for MiDAS.…”

Section: Nature Of Midas Substrates and Why They Persist From Early S...supporting

confidence: 78%

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Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells

et al. 2022

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Section: Nature Of Midas Substrates and Why They Persist From Early S...supporting

confidence: 78%

“…In the latter scenario, G4s are thought to stabilize the R-loops and further impede replication fork progression S3 and S4. Article (Brickner et al, 2022;De Magis et al, 2019;Hamperl and Cimprich, 2014). Therefore, we investigated whether G4s are enriched at the MiDAS sites that coincide with R-loops.…”

Section: Ll Open Accessmentioning

confidence: 99%

Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells

et al. 2022

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“…There are a variety of endogenous sources of replication stress, including abasic sites, DNA bases with modifications (e.g., oxidation, methylation, DNA crosslinks), DNA with secondary structures (e.g., G-quadruplexes, hairpin), DNA-RNA hybrids (R-loops), repetitive sequences with few replication origins, DNA-protein adducts, collision between DNA replication and transcription, and oncogene activation [ 4 , 6 , 58 , 59 ]. Replication stress can also be induced by external sources of genotoxic stress, including UV radiation, which induces DNA intrastrand crosslinks; ionizing radiation (IR), which induces both base damages and DNA breaks; as well as a variety of chemical compounds.…”

Section: Csb-deficient Cells and Their Sensitivity To Replication Str...mentioning

confidence: 99%

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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“…Mutations in the RNase H2 exonuclease complex subunits, commonly associated with the autoinflammatory disorder Aicardi-Goutières syndrome (AGS), and induces STING-mediated inflammation (Crow et al, 2020) due to an accumulation of R-loops (Cristini et al, 2022). R-loops are triple-stranded RNA:DNA hybrid structures occurring naturally in ~5-10% of the genome (Brickner et al, 2022). In this regards, a subset of DEAD-box RNA helicases recognize unusual DNA:RNA structures, functioning to maintain genomic stability, but also serving as critical mediators of immunity (Andrisani et al, 2022; Cargill et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

MEF2A suppresses replicative stress responses that trigger DDX41-dependent IFN production

Smith

Dowling

Karp

et al. 2022

Preprint

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Interferons (IFN) are induced by sensing of self- and non-self DNA or genomic lesions by pathogen recognition receptors (PRR) that activate STING. These pathways must be kept in check by negative regulators to prevent unscheduled activation of IFN, which contributes to autoinflammation. Here we show that MEF2A as a novel negative regulator of inflammation that suppresses homeostatic induction of IFNs. Indeed, MEF2A deficiency results in the spontaneous production of type I IFN and robust downstream IFN-stimulated gene expression that coincided with a robust cellular antiviral state. Mechanistically, MEF2A depletion promoted the accumulation of R-loops that activate the DDX41/STING pathway. This pro-inflammatory pathway was dependent on ATR kinase activity, hallmark of the replicative stress response, was necessary for the activation of STING upon loss of MEF2A expression. Thus, our study connects MEF2A with protection from maladaptive type I IFN responses triggered by R-loop accumulation and links the DDX41-dependent activation of STING to the DNA damage response.

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Walking a tightrope: The complex balancing act of R-loops in genome stability

Cited by 138 publications

References 280 publications

Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells

Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

MEF2A suppresses replicative stress responses that trigger DDX41-dependent IFN production

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