Hypoxia-induced SETX links replication stress with the unfolded protein response

Ramachandran, Shaliny; Tiffany, Stephen T.; Griffin, Jon; Ng, Natalie; Foskolou, Iosifina P.; Hwang, Ming-Shih; Victori, Pedro; Cheng, Wei-Chen; Buffa, Francesca M.; Leszczynska, Katarzyna B.; El‐Khamisy, Sherif F.; Gromak, Natalia; Hammond, Ester M.

doi:10.1038/s41467-021-24066-z

Cited by 25 publications

(30 citation statements)

References 75 publications

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“…The RNA or RNA/DNA helicases Ddx1, Ddx3x, Ddx5, Ddx18, Ddx21, Ddx27, Ddx39b, Dhx9, Dhx15, Srsf1, Xrn2 and Prkdc are all components of the R-loop interactome and were all found to have reduced chromatin accessibility in their promoters in hypoxia (Figure 2A, Supplementary Table 5) 29 . Of these helicases, we have shown previously that DHX9 mRNA expression is repressed in hypoxia (<0.1% O2) therefore supporting a link between these ATACseq data and gene expression in hypoxia (Figure 2B) 7 . In contrast, chromatin accessibility did not change at the SETX gene promoter (Supplementary Figure 2E), consistent with the recently identified increase in SETX expression in response to hypoxia (<0.1% O2) 7 .…”

Section: Resultssupporting

confidence: 78%

“…Of these helicases, we have shown previously that DHX9 mRNA expression is repressed in hypoxia (<0.1% O2) therefore supporting a link between these ATACseq data and gene expression in hypoxia (Figure 2B) 7 . In contrast, chromatin accessibility did not change at the SETX gene promoter (Supplementary Figure 2E), consistent with the recently identified increase in SETX expression in response to hypoxia (<0.1% O2) 7 .…”

Section: Resultssupporting

confidence: 78%

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Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation

Leszczynska

Dzwigonska

Estephan

et al. 2022

Preprint

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Local hypoxia (low oxygen) occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most of the prior research has focused on hypoxia-inducible genes in hypoxia as opposed to those which are decreased. Using ATACseq, we demonstrate that chromatin accessibility is decreased in an oxygen-dependent manner, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing and the R-loop interactome. As R-loops accumulate in hypoxic conditions we hypothesized that an underlying mechanism could be the repression of the R-loop interactome. One of the genes with decreased chromatin accessibility in hypoxia was DDX5, encoding the RNA helicase, DDX5, which showed reduced expression in various cancer cell lines in hypoxic conditions, tumor xenografts and in patient samples with hypoxic tumors. In addition, we identified TRIM5 as a novel hypoxia inducible E3 ligase which targets DDX5 for proteasomal degradation independently of changes at mRNA levels. We demonstrate multiple mechanisms contributing to reduced DDX5 expression in hypoxic conditions. Most interestingly, we found that when DDX5 is rescued in hypoxia, R-loop levels accumulate further, therefore demonstrating that hypoxia-mediated repression of DDX5 restricts R-loop accumulation. Together these data support the hypothesis that a critical part of the biological response to hypoxia is the repression of multiple R-loop processing factors, however, as shown for DDX5, their role is specific and distinct.

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Section: Resultssupporting

confidence: 78%

Section: Resultssupporting

confidence: 78%

Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation

Leszczynska

Dzwigonska

Estephan

et al. 2022

Preprint

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“…Thus, a combination of CPT and mitoxantrone may offer a new targeted approach to treat certain cancers. Reduction of SETX levels via USP11 inhibition could also overcome cancer resistance caused by hypoxia 27 . Furthermore, as USP11 regulates SETX protein stability, mitoxantrone could be used to treat disorders where SETX is overexpressed or where its activity and levels are pathogenic.…”

Section: Discussionmentioning

confidence: 99%

“…The ALS4 SETX L389S variant was shown to resolve R-loops at 1200 human promoters leading to transcriptional misregulation 26 . Furthermore, we recently reported a role for SETX in cancer, by protecting cells from R-loop-mediated DNA damage in hypoxia, which is a major cause of resistance to anti-cancer therapeutics 27 .…”

Section: Introductionmentioning

confidence: 99%

USP11 controls R-loops by regulating senataxin proteostasis

et al. 2021

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R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the R-loop-specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease.

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“…On the other hand, hypoxia induced Senataxin, an RNA-DNA hybrid helicase, in a PERK-dependent manner. Senataxin decreases the numbers of DNA-DNA hybrids and protects cells from DNA damages (Ramachandran et al, 2021).…”

Section: Crosstalk Between the Replication Stress Checkpoint And General Biological Stressesmentioning

confidence: 99%

Roles of Claspin in regulation of DNA replication, replication stress responses and oncogenesis in human cells

Hsiao

Yang

Masai

2021

GENOME INSTAB. DIS.

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Human cells need to cope with the stalling of DNA replication to complete replication of the entire genome to minimize genome instability. They respond to “replication stress” by activating the conserved ATR-Claspin-Chk1 replication checkpoint pathway. The stalled replication fork is detected and stabilized by the checkpoint proteins to prevent disintegration of the replication fork, to remove the lesion or problems that are causing fork block, and to facilitate the continuation of fork progression. Claspin, a factor conserved from yeasts to human, plays a crucial role as a mediator that transmits the replication fork arrest signal from the sensor kinase, ataxia telangiectasia and Rad3-related (ATR), to the effector kinase, Checkpoint kinase 1 (Chk1). Claspin interacts with multiple kinases and replication factors and facilitates efficient replication fork progression and initiation during the normal course of DNA replication as well. It interacts with Cdc7 kinase through the acidic patch segment near the C-terminus and this interaction is critical for efficient phosphorylation of Mcm in non-cancer cells and also for checkpoint activation. Phosphorylation of Claspin by Cdc7, recruited to the acidic patch, regulates the conformation of Claspin through affecting the intramolecular interaction between the N- and C-terminal segments of Claspin. Abundance of Claspin is regulated at both mRNA and protein levels (post-transcriptional regulation and protein stability) and affects the extent of replication checkpoint. In this article, we will discuss how the ATR-Claspin-Chk1 regulates normal and stressed DNA replication and provide insight into the therapeutic potential of targeting replication checkpoint for efficient cancer cell death.

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Hypoxia-induced SETX links replication stress with the unfolded protein response

Cited by 25 publications

References 75 publications

Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation

Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation

USP11 controls R-loops by regulating senataxin proteostasis

Roles of Claspin in regulation of DNA replication, replication stress responses and oncogenesis in human cells

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