The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage

Shostak, Kateryna; Jiang, Zheshen; Charloteaux, Benoît; Mayer, Alice; Habraken, Yvette; Tharun, Lars; Klein, Sebastian; Xu, Xiaowei; Duong, Hong Quan; Vislovukh, A. A.; Close, Pierre; Florin, Alexandra; Rambow, Florian; Marine, Jean–Christophe; Büttner, Reinhard; Chariot, Alain

doi:10.1038/s41467-020-15003-7

Cited by 35 publications

(26 citation statements)

References 63 publications

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“…The loss of E3 ubiquitin–protein ligase ring finger protein 113A (RNF113A) triggers DNA damage-related ferroptosis. 125 Lon peptidase 1, mitochondrial (LONP1) is an essential stress response protease that mediates mitochondrial proteostasis. LONP1-mediated degradation of transcription factor A, mitochondrial (TFAM) induces mitochondrial DNA damage, which causes ferroptosis in pancreatic cancer cells through the activation of stimulator of interferon response CGAMP interactor 1 (STING1/TMEM173)-dependent autophagy.…”

Section: Degradation Systemsmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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Section: Degradation Systemsmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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“…Very recently, another study has shown that RNF113A is recruited to sites of DNA damage and found that RNF113A is important for regulating DNA repair factor recruitment to chromatin [ 115 ]. This work also showed that RNF113A co-localized with phosphorylated DNA-PK cs in cisplatin-treated cells [ 115 ], however as our study did not look at interaction in the context of double-stranded breaks, it is presently unclear why this protein may be found in proximity to Ku70. We have previously found that Ku appears to be in close proximity to many DNA repair factors and sensors, even in the absence of DNA damage [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Ku70 Domain-Specific Interactors Using BioID2

Abbasi

Schild-Poulter

2021

Cells

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Since its inception, proximity-dependent biotin identification (BioID), an in vivo biochemical screening method to identify proximal protein interactors, has seen extensive developments. Improvements and variants of the original BioID technique are being reported regularly, each expanding upon the existing potential of the original technique. While this is advancing our capabilities to study protein interactions under different contexts, we have yet to explore the full potential of the existing BioID variants already at our disposal. Here, we used BioID2 in an innovative manner to identify and map domain-specific protein interactions for the human Ku70 protein. Four HEK293 cell lines were created, each stably expressing various BioID2-tagged Ku70 segments designed to collectively identify factors that interact with different regions of Ku70. Historically, although many interactions have been mapped to the C-terminus of the Ku70 protein, few have been mapped to the N-terminal von Willebrand A-like domain, a canonical protein-binding domain ideally situated as a site for protein interaction. Using this segmented approach, we were able to identify domain-specific interactors as well as evaluate advantages and drawbacks of the BioID2 technique. Our study identifies several potential new Ku70 interactors and validates RNF113A and Spindly as proteins that contact or co-localize with Ku in a Ku70 vWA domain-specific manner.

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“…Since we previously found that recombinant RNF113A showed no E3 activity (Brickner et al, 2017), we used RNF113A complex purified from HeLa-S cell nuclear extracts, as above, and tested the ability of methylated RNAs to induce its E3 ligase activity. Due to its association with the spliceosome (Hegele et al, 2012;Shostak et al, 2020), we first used in vitro transcribed bglobin pre-mRNA (Movassat et al, 2014) as a potential substrate for inducing RNF113A E3 activity. While the unmodified RNA had a mild stimulatory effect on the E3 activity of RNF113A, we saw a marked increase in the E3 activity when the same RNA was premethylated using dimethyl sulphate (DMS; Figure 5A).…”

Section: In Vitro Activation Of Rnf113a E3 Ligase By Methylated Rnamentioning

confidence: 99%

Aberrant RNA methylation triggers recruitment of an alkylation repair complex

Brickner¹,

Tsao²,

Rodell³

et al. 2020

Preprint

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SummaryA critical question in genome stability is the nature of the chemical damage responsible for repair activation. We previously reported a novel pathway specifically activated during alkylation damage in human cells, where the E3 ubiquitin ligase RNF113A mediates the recruitment of the ASCC repair complex. Yet the mechanistic basis for the alkylation damage selectivity of this pathway remains unclear. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. This aberrant RNA methylation causes transcriptional repression in a manner dependent on the ASCC complex. We show that an alkylated pre-mRNA, or an RNA containing a single damaged base, is sufficient to activate RNF113A E3 activity in a phosphorylation-dependent manner. Together, our work identifies an unexpected role for RNA damage in eliciting a DNA repair response, and suggests that RNA may serve as the “canary in the coal mine” for sensing alkylation damage.

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The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage

Cited by 35 publications

References 63 publications

Ferroptosis: molecular mechanisms and health implications

Ferroptosis: molecular mechanisms and health implications

Identification of Ku70 Domain-Specific Interactors Using BioID2

Aberrant RNA methylation triggers recruitment of an alkylation repair complex

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