hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Pabla, Navjotsingh; Ma, Zhigui; McIlhatton, Michael A.; Fishel, Richard; Dong, Zheng

doi:10.1074/jbc.m110.210989

Cited by 83 publications

(81 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…53,54 In cisplatin AKI, p53 is induced via the DNA damage response mediated by ATR/Chk2. 55,56 However, in ischemic AKI, the ATM-mediated DNA damage response may be responsible. 47 p53 may activate the transcription and expression of p21 to arrest the cell cycle.…”

Section: Receptorsmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

Self Cite

176

151

View full text Add to dashboard Cite

In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

show abstract

Section: Receptorsmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

Self Cite

176

151

View full text Add to dashboard Cite

show abstract

“…Several genes involved in the MMR pathway have dual roles in apoptosis as well as DNA repair. For example, mismatch repair protein MSH2 is involved in DNA damageinduced apoptosis by recruiting ataxia telangiectasia-and Rad3-related protein (ATR) to DNA damage sites for its activities in apoptosis (Pabla et al, 2011). Experimental evidence from MSH2-deficient mice also suggest that the MMR system has dual functions of avoiding mutagenesis and inducing apoptosis to inhibit oxidative stress-induced tumorigenesis (Piao et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism

2015

View full text Add to dashboard Cite

Renal cell carcinoma is the most common form of kidney cancer and is highly resistant to chemotherapy. Although the role of oxidative stress in kidney cancer is known, the chemotherapeutic response of cancer cells adapted to chronic oxidative stress is not clear. Hence, the effect of oxidative stress on sensitivity to doxorubicin-induced cytotoxicity was evaluated using an in vitro model of human kidney cancer cells adapted to chronic oxidative stress. Results of MTT-and anchorage-independent growth assays and cell cycle analysis revealed significant decrease in sensitivity to doxorubicin in Caki-1 cells adapted to oxidative stress. Changes in the expression of genes involved in drug transport, cell survival, and DNA repair-dependent apoptosis further confirmed increased resistance to doxorubicin-induced cytotoxicity in these cells. Decreased expression of mismatch repair (MMR) gene MSH2 in cells exposed to oxidative stress suggests that loss of MMR-dependent apoptosis could be a potential mechanism for increased resistance to doxorubicin-induced cytotoxicity. Additionally, downregulation of HDAC1, an increase in the level of histone H3 acetylation, and hypermethylation of MSH2 promoter were also observed in Caki-1 cells adapted to chronic oxidative stress. DNA-demethylating agent 5-Aza-2dC significantly restored the expression of MSH2 and doxorubicin-induced cytotoxicity in Caki-1 cells adapted to chronic oxidative stress, suggesting the role of DNA hypermethylation in inactivation of MSH2 expression and consequently MMRdependent apoptosis in these cells. In summary, this study for the first time provides direct evidence for the role of oxidative stress in chemotherapeutic resistance in renal carcinoma cells potentially through epigenetic mechanism.

show abstract

“…hMSH2 directly participates in ATR recruitment and activation, leading to DNA damage signaling and subsequent apoptosis. Therefore, hMSH2 deficiency increases the resistance of cells to apoptosis (17). Another study suggests that the nuclear isoforms of hMYH initiate cell death by sensing adenine opposite 8-oxoG during nuclear DNA replication, thus suppressing tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, hMSH2-deficient cells are more resistant to apoptosis (17). The mismatch repair and MYH repair pathways share many common features.…”

Section: Introductionmentioning

confidence: 99%

Human MutY homolog induces apoptosis in etoposide-treated HEK293 cells

et al. 2012

View full text Add to dashboard Cite

Abstract. Etoposide (ETP) treatment of ataxia telangiectasia mutated (ATM) and Rad3-related protein (ATR)-, topoisomerase-binding protein-1 (TopBP1) and human MutY homolog (hMYH)-depleted cells results in a significant reduction in apoptotic signaling. The association between ATR or TopBP1 and hMYH increased following ETP treatment. In hMYH knockdown cells, the interaction between ATR and TopBP1 decreased following ETP treatment. We suggest that hMYH functions as a sensor of ETP-induced apoptosis. The results suggest that in the absence of hMYH, cells are unable to recognize the damage signal and the ATR pathway is not activated.

show abstract

hMSH2 Recruits ATR to DNA Damage Sites for Activation during DNA Damage-induced Apoptosis

Cited by 83 publications

References 44 publications

Cellular and Molecular Mechanisms of AKI

Cellular and Molecular Mechanisms of AKI

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism

Human MutY homolog induces apoptosis in etoposide-treated HEK293 cells

Contact Info

Product

Resources

About