PARP1-mediated PARylation of TonEBP prevents R-loop–associated DNA damage

Ye, Byeong Jin; Kang, Hye-Won; Lee-Kwon, Whaseon; Kwon, Hyug Moo; Choi, Soo Youn

doi:10.1016/j.dnarep.2021.103132

Cited by 22 publications

(15 citation statements)

References 40 publications

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“…4c , yellow). Among the genes that overlap between the IP-MS RF and Prox-MS RF datasets are known R-loop regulators involved in RNA processing, such as SF3A3 and SRSF2 ( Li and Manley 2005 ; Tanikawa et al 2016 ; Singh et al 2020 ), as well as DNA replication and repair proteins like MCM6 and PARP1 ( Vijayraghavan et al 2016 ; Ye et al 2021 ). Given the many literature connections to R-loops within this small overlapping group, we consider it a very high confidence set of genes.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, our group and others have found that members of the BAF chromatin remodeling complexes play roles in preventing R-loop associated replication stress ( Bayona-Feliu et al 2021 ; Tsai et al 2021 ) and our RLBP list predicts that both catalytic and accessory BAF subunits are R-loop binding candidates. Additional hits include the DDX23 helicase that plays a crucial role in the regulation of RNAPII pausing to prevent harmful R-loop accumulation ( Sridhara et al 2017 ), PARP1 (also identified in Cristini et al ) which functions in the protection against R-loop associated DNA damage through its interactions with DHX9 and TonEBP ( Ye et al 2021 ), and more. In general then, previously recognized R-loop regulators, including those not included in the training set, score very highly in our analysis.…”

Section: Discussionmentioning

confidence: 99%

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Integrative analysis and prediction of human R-loop binding proteins

Kumar

Fournier

Stirling

2022

G3 Genes|Genomes|Genetics

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In the past decade there has been a growing appreciation for R-loop structures as important regulators of the epigenome, telomere maintenance, DNA repair and replication. Given these numerous functions, dozens, or potentially hundreds, of proteins could serve as direct or indirect regulators of R-loop writing, reading, and erasing. In order to understand common properties shared amongst potential R-loop binding proteins (RLBPs) we mined published proteomic studies and distilled 10 features that were enriched in RLBPs compared to the rest of the proteome. Applying an easy-ensemble machine learning approach, we used these RLBP-specific features along with their amino acid composition to create random forest classifiers that predict the likelihood of a protein to bind to R-loops. Known R-loop regulating pathways such as splicing, DNA damage repair and chromatin remodeling are highly enriched in our datasets, and we validate two new R-loop binding proteins LIG1 and FXR1 in human cells. Together these datasets provide a reference to pursue analyses of novel R-loop regulatory proteins.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrative analysis and prediction of human R-loop binding proteins

Kumar

Fournier

Stirling

2022

G3 Genes|Genomes|Genetics

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“…Of note, TREX1 has been shown to translocate into the nucleus upon DNA damage and to interact with PARP1, a nuclear enzyme involved in the DNA damage response ( Miyazaki et al, 2014 ). Interestingly, PARP1 has been recently implicated in preventing R-loop–associated DNA damage through PARylation of TonEBP ( Ye et al, 2021 ), and PARP1 interacts with RNA/DNA helicase DHX9 and R-loops in vivo, preventing R-loop–associated DNA damage ( Cristini et al, 2018 ). It will be of interest to explore if there is a direct link between loss of TREX1 and R-loop homeostasis.…”

Section: Discussionmentioning

confidence: 99%

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

Giordano

Luciani

Gatto

et al. 2022

Journal of Experimental Medicine

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Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.

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“…PARP1 plays a crucial role in repairing transcription-coupled single- and double-strand breaks (Zhao et al, 2022) and has been shown to play an essential role in R-loop prevention and resolution (Cristini et al, 2018; Lin et al, 2022; Ye et al, 2021). PARP1 was one of the significant interactors with PSIP1/p75 and was also enriched in the R-loop proteome (Cristini et al, 2018; Sundarraj et al, 2021) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Several proteins involved in transcription, RNA processing and DNA repairs, such as the PARP1, TFIIS, BRCA1, THO complex, SRSF1, DDX23, SETX, DHX9, TOP1 and others, are known to reduce R-loop burden and genome instability (Alonso and Noordermeer, 2021;Chen et al, 2018;Katyal et al, 2014;Ye et al, 2021;Zatreanu et al, 2019b;Zhao et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity

Jayakumar

Patel

Aziz

et al. 2022

Preprint

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Accumulation of R-loops, which are transcriptional by-products, poses a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a chromatin protein, shown to have histone chaperone activity and interact with transcriptional elongation complex. Here, we demonstrated that PSIP1 interacts with R-loops and with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells increase R-loop and DNA damage levels at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest and reduced replication rate. In addition, we demonstrate that targeting PSIP1 increases the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA-damaging agents. Overall, our findings reveal the critical role of PSIP1 in maintaining genome stability by reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.

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PARP1-mediated PARylation of TonEBP prevents R-loop–associated DNA damage

Cited by 22 publications

References 40 publications

Integrative analysis and prediction of human R-loop binding proteins

Integrative analysis and prediction of human R-loop binding proteins

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity

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