PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

Li, Caiyun G.; Mahon, Cathal; Sweeney, Nathaly M.; Verschueren, Erik; Kantamani, Vivek; Li, Dan; Hennigs, Jan K.; Marciano, David; Diebold, Isabel; Abu-Halawa, Ossama; Elliott, Matthew; Sa, Silin; Guo, Feng; Wang, Lingli; Cao, Aiqin; Guignabert, Christophe; Sollier, Julie; Nickel, Nils; Kaschwich, Mark; Cimprich, Karlene A.; Rabinovitch, Marlene

doi:10.1016/j.celrep.2019.01.013

Cited by 60 publications

(46 citation statements)

References 58 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this axis is dysfunctional in PAH-PAECs, with reduced PPAR-γ-UBR5 interaction, elevated ATMIN which leads to progressive DNA damage, and impaired repair in these cells ( Figure 2 ). Consistent with the in vitro pathway findings, the results were validated in PAH-PAECs and PAH-lung tissues [ 65 ]. Furthermore, the reduction of ATMIN in PAH-PAECs reduced synthetic DNA damage comparable to the control cells.…”

Section: Dna Repair Pathways and Cell Cycle Checkpoints In Pahsupporting

confidence: 82%

“…At present, there is not enough evidence to draw conclusions on the status of different DNA repair pathways in PAH. There are reports suggesting amplified DDR in PAH-PASMCs [ 49 , 67 ], while a few stand in contradiction ( Table 1 : OGG1, RAD51), reporting reduced DDR in PAH-PAECs [ 47 , 65 , 89 ] under different DNA damaging environments ( Table 1 ). One of the major reasons behind this gap is a lack of paired cell types from the patients in the same study, as well as replication of the findings across different types of PAH.…”

Section: Discussionmentioning

confidence: 99%

“…In PAECs and PASMCs, PPAR-γ promotes cell survival and suppresses proliferation via interaction with Apelin [ 64 ]. Using an unbiased proteomics approach, Li and colleagues showed that PPAR-γ interacts with MRN (MRE-11-RAD50-NBS1), promoting ATM signaling, and is also essential for UBR5 activity targeting ATM interactor (ATMIN) [ 65 ]. Hence, upon DNA damage, ATMIN is degraded by UBR5, leading to ATM activation.…”

Section: Dna Repair Pathways and Cell Cycle Checkpoints In Pahmentioning

confidence: 99%

See 2 more Smart Citations

DNA Damage and Repair in Pulmonary Arterial Hypertension

Sharma

Aldred

2020

Genes

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with both genetic and environmental dynamics contributing to disease progression. Over the last decade, several studies have demonstrated the presence of genomic instability and increased levels of DNA damage in PAH lung vascular cells, which contribute to their pathogenic apoptosis-resistant and proliferating characteristics. In addition, the dysregulated DNA damage response pathways have been indicated as causal factors for the presence of persistent DNA damage. To understand the significant implications of DNA damage and repair in PAH pathogenesis, the current review summarizes the recent advances made in this field. This includes an overview of the observed DNA damage in the nuclear and mitochondrial genome of PAH patients. Next, the irregularities observed in various DNA damage response pathways and their role in accumulating DNA damage, escaping apoptosis, and proliferation under a DNA damaging environment are discussed. Although the current literature establishes the pertinence of DNA damage in PAH, additional studies are required to understand the temporal sequence of the above-mentioned events. Further, an exploration of different types of DNA damage in conjunction with associated impaired DNA damage response in PAH will potentially stimulate early diagnosis of the disease and development of novel therapeutic strategies.

show abstract

Section: Dna Repair Pathways and Cell Cycle Checkpoints In Pahsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Dna Repair Pathways and Cell Cycle Checkpoints In Pahmentioning

confidence: 99%

See 1 more Smart Citation

DNA Damage and Repair in Pulmonary Arterial Hypertension

Sharma

Aldred

2020

Genes

View full text Add to dashboard Cite

show abstract

“…UBR5 is a member of the E3 ubiquitin ligases, which are key regulators in the ubiquitin-proteasome system (6,7). In addition, UBR5 interacts with several proteins and signaling pathways involved in a wide variety of cellular processes, including the cell cycle, transcriptional and translational machinery (9,14,28,29). The PI3K/Akt signaling pathway is associated with cell survival and proliferation in various types of cancer (14,30), indicating that the role of UBR5 in gastric cancer proliferation may be mediated via the PI3K/Akt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

UBR5 oncogene as an indicator of poor prognosis in gastric cancer

et al. 2020

View full text Add to dashboard Cite

The human ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene, which is localized to chromosome 8q22, encodes an ~10 kb mRNA and a >300 kDa protein, which can be detected in a number of cell types. UBR5 is implicated in several types of cancer, including ovarian cancer, gallbladder cancer and lymphoma; however, its role in gastric cancer is not completely understood. In the present study, the expression levels of UBR5 in human gastric cancer tissues and cell lines were examined via immunohistochemistry, reverse transcription-quantitative PCR analysis and western blotting. Furthermore, the association between UBR5 expression and clinicopathological characteristics, as well as the prognosis of patients with gastric cancer, were examined. In addition, the role of UBR5 in gastric cancer cell proliferation, invasion and migration was investigated by conducting MTS, Transwell and wound healing assays, respectively. The results indicated that the mRNA and protein expression levels of UBR5 were significantly increased in gastric cancer tissues compared with para-carcinoma tissues. High UBR5 expression levels were significantly associated with larger tumor size, advanced TNM stage and lymph node metastasis. In addition, high UBR5 expression indicated a poor prognosis in patients with gastric cancer. Furthermore, in vitro experiments demonstrated that UBR5 knockdown was associated with reduced HGC-27 gastric cancer cell proliferation, invasion and migration compared with the small interfering RNA control group. Therefore, the results indicated that UBR5 may serve a key role in gastric cancer, indicating that UBR5 may also serve as an important prognostic biomarker.

show abstract

“…A delicate balance must be struck, however, as evidenced by the fact that mere inhibition of Ku70, by either decreased phosphorylation 27 directly or epigenetic regulation 28 , results in protection against development of PH. Similarly, expression of the DNA damage response sensors MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5, necessary for promoting endothelial cell health under homeostatic conditions, predisposes to development of PH 29 . Finally, overexpression of Nudix hydrolase 1 (NUDT1), a detoxifying DNA enzyme, results in increased incorporation of oxidized nucleotides into DNA, promoting apoptosis resistance and proliferation secondary to DNA damage 30 ; NUDT1 inhibitors have been shown to block development of PH in the monocrotaline and sugen/hypoxia rat models.…”

Section: Dna Sensing and Its Role In Pulmonary Hypertensionmentioning

confidence: 99%

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

et al. 2021

View full text Add to dashboard Cite

For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic ma-terial, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of nucleotide sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expres-sion of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condi-tion is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circula-tion of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immu-nology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

show abstract

PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

Cited by 60 publications

References 58 publications

DNA Damage and Repair in Pulmonary Arterial Hypertension

DNA Damage and Repair in Pulmonary Arterial Hypertension

UBR5 oncogene as an indicator of poor prognosis in gastric cancer

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

Contact Info

Product

Resources

About