MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling

Espinosa‐Díez, Cristina; Wilson, RaeAnna; Chatterjee, Namita; Hudson, Clayton; Ruhl, Rebecca; Subbiah, Ramesh; Helms, Erin J.; Khan, Omar F.; Anderson, Daniel G.; Anand, Sudarshan

doi:10.1101/132258

Cited by 6 publications

(12 citation statements)

References 57 publications

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“…We previously showed that miR-494 is responsive to radiation and chemical inducers of genotoxic stress and functions to increase endothelial senescence during DNA damage responses (24). Given the intricate relationship between radiation, oxidative stress and ER stress (14,17), we asked if ER stress affected miR-494 expression and function.…”

Section: Er Stress Induces Mir-494 In Vitromentioning

confidence: 99%

“…miRs typically are thought to regulate numerous targets in a context dependent manner. We have previously shown that miR-494 targets the Mre11a, Rad50, Nbn (MRN) complex in the DNA damage repair pathway in response to genotoxic stressors (24). To identify the targets relevant for miR-494 in the context of ER stress, we undertook a proteomics-based approach.…”

Section: Mass Spectrometry Identifies Putative Targets Of Mir-494 Relmentioning

confidence: 99%

“…Our previous work identified a cohort of miRs that are induced by DNA damage in ECs (24,31,32). We further characterized one of these miRs, miR-494, as a regulator of endothelial senescence in response to genotoxic stressors (24).…”

Section: Introductionmentioning

confidence: 97%

“…MicroRNAs (miRs) are small non-coding RNAs that are critical regulators of physiological and pathological stress responses (18,19). We, and others have shown that specific miRs regulate EC responses to numerous effectors including: angiogenic growth factors (20,21), hypoxia (22,23), DNA damage (24), and oxidative stress (25). Furthermore, specific miRs have been identified as modulators of ER stress in different models of disease (26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

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A miR-494 dependent feedback loop regulates ER stress

Chatterjee¹,

Espinosa‐Díez²,

Anand³

2020

Preprint

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Defects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here we show that miR-494 plays a functional role during ER stress. ER stress inducers (tunicamycin & thapsigargin) robustly increase the expression of miR-494 in vitro in an ATF6 dependent manner.Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to tunicamycin in endothelial cells. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both tunicamycin and miR-494. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene BIRC5 (survivin) as one of the targets of miR-494 during ER stress. Finally, induction of ER stress in vivo increases miR-494 expression in the liver. Pretreatment of mice with a miR-494 plasmid via hydrodynamic injection decreased ER stress in response to tunicamycin in part by decreasing inflammatory chemokines and cytokines. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling. We propose that RNA-based approaches targeting miR-494 or its targets may be attractive candidates for inhibiting ER stress dependent pathologies in human disease.

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Section: Er Stress Induces Mir-494 In Vitromentioning

confidence: 99%

Section: Mass Spectrometry Identifies Putative Targets Of Mir-494 Relmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A miR-494 dependent feedback loop regulates ER stress

Chatterjee¹,

Espinosa‐Díez²,

Anand³

2020

Preprint

Self Cite

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“…Depending on how severe the damage is, endothelial cells (ECs) make quick decisions among cell death, cell cycle arrest or survival. We have demonstrated how the expression of specific group of miRs can influence endothelial fate [1,2] in the context of DNA damage responses. However, the role of long non-coding RNAs (lncRNAs) in the endothelial stress responses is unclear.…”

mentioning

confidence: 99%

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Espinosa‐Díez¹,

Wilson²,

Mukherjee³

et al. 2018

Preprint

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Changes in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

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Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers

et al. 2021

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The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.

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MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling

Cited by 6 publications

References 57 publications

A miR-494 dependent feedback loop regulates ER stress

A miR-494 dependent feedback loop regulates ER stress

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers

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