Nucleotide Excision Repair-dependent DNA Double-strand Break Formation and ATM Signaling Activation in Mammalian Quiescent Cells

Wakasugi, Mitsuo; Sasaki, Takuma; Matsumoto, Megumi; Nagaoka, Mika; Inoue, Keiko; Inobe, Manabu; Horibata, Katsuyoshi; Tanaka, Kiyoji; Matsunaga, Tsukasa

doi:10.1074/jbc.m114.589747

Cited by 48 publications

(62 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, CHK1 protein levels were nearly absent in the noncycling cells (Fig. 1A), consistent with previous reports in other cell lines (29,32). Nonetheless, this difference in phosphorylation between cycling and non-cycling cells (Fig.…”

Section: Uv-induced Dna Damage Signaling Exhibit Different Profiles Isupporting

confidence: 82%

“…ATM and ATR Both Contribute to Canonical DNA Damage Signaling Events in UV-irradiated Non-cycling Cells-A recent study found that UV irradiation of non-cycling cells leads to formation of double-strand breaks in DNA in a nucleotide excision repair-dependent manner (29). This double-strand break response was associated with the activation of ATM and the phosphorylation of both H2AX and the more specific ATM substrate CHK2.…”

Section: Atr Contributes To Dna Damage Response Protein Phosphorylatimentioning

confidence: 99%

“…Although ATR activation has been suggested to occur in non-cycling cells (25)(26)(27)(28)(29)(30)(31)(32)(33), its signaling function has not been extensively examined and its bona fide substrates are not known. Thus, to examine the role of ATR kinase activity in DNA damage signaling in non-cycling cells, we made use of the highly selective ATR inhibitor VE-821 (21,53).…”

Section: Atr Contributes To Dna Damage Response Protein Phosphorylatimentioning

confidence: 99%

“…Non-cycling Cells-Previous studies comparing UV-induced DNA damage signaling in cycling and noncycling cells have been rather limited (29,32). Thus, to examine this issue in greater detail and specifically the contribution of the ATR kinase, we monitored the phosphorylation of several key DNA damage response signaling proteins following UV irradiation of rapidly growing, subconfluent HaCaT keratinocytes (cycling cells) and cells grown to confluence and maintained in low serum (non-cycling cells).…”

Section: Uv-induced Dna Damage Signaling Exhibit Different Profiles Imentioning

confidence: 99%

“…Although previous studies have indicated that ATR can be activated in noncycling cells in response to DNA repair intermediates (25)(26)(27)(28)(29)(30)(31)(32) and in response to the stalling of RNA polymerase (33)(34)(35), the functional significance of ATR in these contexts in non-cycling cells has not been examined.…”

mentioning

confidence: 99%

See 4 more Smart Citations

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Kemp

Sancar

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected nonreplicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens.Ultraviolet (UV) photoproducts and other bulky DNA lesions block the progression of DNA and RNA polymerases and lead to the activation of various DNA damage responses that are regulated by the action of the ataxia telangiectasia and Rad-3-related (ATR) 3 protein kinase. For example, in response to DNA polymerase stalling and uncoupling from DNA helicase activity (1), ATR is thought to be recruited to singlestranded regions of DNA where it promotes a number of DNA metabolic processes that maintain genomic integrity (2-6), including replication fork stabilization, DNA synthesis and lesion bypass, homologous recombination, replication origin firing, and cell cycle delay. The importance of ATR kinase activity in these responses in replicating cells is evidenced by the fate of cells in which the catalytic activity of ATR has been genetically or pharmacologically inhibited following replication stress, which include apoptosis and entry into catastrophic mitoses (7-10). Thus, ATR helps replicating cells cope with DNA damage and replication stress by facilitating cellular processes that maintain genomic stability and avoid cell death. Given these features of ATR, there has been great interest in the development and use of selective small-molecule inhibitors of ATR kinase activity in cancer chemotherapy regimens in conjunction with compounds that damage DNA and generate replication stress (11-13). For example, several studies have shown that ATR inhibition sensitizes cancer cells to cell kill...

show abstract

Section: Uv-induced Dna Damage Signaling Exhibit Different Profiles Isupporting

confidence: 82%

Section: Atr Contributes To Dna Damage Response Protein Phosphorylatimentioning

confidence: 99%

Section: Atr Contributes To Dna Damage Response Protein Phosphorylatimentioning

confidence: 99%

Section: Uv-induced Dna Damage Signaling Exhibit Different Profiles Imentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Kemp

Sancar

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

Khan

Travers

Kemp

2018

Environ and Mol Mutagen

112

View full text Add to dashboard Cite

The growing incidence of melanoma is a serious public health issue that merits a thorough understanding of potential causative risk factors, which includes exposure to ultraviolet radiation (UVR). Though UVR has been classified as a complete carcinogen and has long been recognized for its ability to damage genomic DNA through both direct and indirect means, the precise mechanisms by which the UVA and UVB components of UVR contribute to the pathogenesis of melanoma have not been clearly defined. In this review, we therefore highlight recent studies that have addressed roles for UVA radiation in the generation of DNA damage and in modulating the subsequent cellular responses to DNA damage in melanocytes, which are the cell type that gives rise to melanoma. Recent research suggests that UVA not only contributes to the direct formation of DNA lesions but also impairs the removal of UV photoproducts from genomic DNA through oxidation and damage to DNA repair proteins. Moreover, the melanocyte microenvironment within the epidermis of the skin is also expected to impact melanomagenesis, and we therefore discuss several paracrine signaling pathways that have been shown to impact the DNA damage response in UV-irradiated melanocytes. Lastly, we examine how alterations to the immune microenvironment by UVA-associated DNA damage responses may contribute to melanoma development. Thus, there appear to be multiple avenues by which UVA may elevate the risk of melanoma. Protective strategies against excess exposure to UVA wavelengths of light therefore have the potential to decrease the incidence of melanoma. Environ. Mol. Mutagen. 59:438-460, 2018. © 2018 Wiley Periodicals, Inc.

show abstract

Solar ultraviolet‐induced DNA damage response: Melanocytes story in transformation to environmental melanomagenesis

Sarkar

Gaddameedhi

2020

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

Nucleotide Excision Repair-dependent DNA Double-strand Break Formation and ATM Signaling Activation in Mammalian Quiescent Cells

Cited by 48 publications

References 38 publications

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

Solar ultraviolet‐induced DNA damage response: Melanocytes story in transformation to environmental melanomagenesis

Contact Info

Product

Resources

About