ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1

Hilton, Benjamin; Li, Zhengke; Musich, Phillip R.; Wang, Hui; Cartwright, Brian M.; Serrano, Moises A.; Zhou, Xiao Zhen; Lu, Kun Ping; Zou, Yue

doi:10.1016/j.molcel.2015.08.008

Cited by 85 publications

(101 citation statements)

References 52 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We note that this dependence on ATR kinase activity differentiates our findings from a recent report that a fraction of ATR directly localizes to mitochondria to inhibit apoptosis in a manner that does not require its kinase activity (72). Thus, the proapoptotic function of ATR kinase described here is unlikely to be due to a function at the mitochondria.…”

Section: Atr Promotes Apoptotic Signaling In Non-cycling Cells Insupporting

confidence: 72%

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: Atr Promotes Apoptotic Signaling In Non-cycling Cells Insupporting

confidence: 72%

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

“…Phosphorylation of TSC1 would in turn activate mTORC1 Li et al, 2018). While it is mostly nuclear, multiple recent publications have shown a small fraction of ATR in the cytoplasm (Hilton et al, 2016;Postigo et al, 2017). We found that ATR is expressed at a higher level in the cytoplasmic fraction of senescent bypassed cells compared to senescent cells (Fig.…”

Section: Atr Activates Mtorc1 To Increase Nucleotide Synthesissupporting

confidence: 49%

Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming

Buj

Chen

Dahl

et al. 2018

Preprint

View full text Add to dashboard Cite

2 SummaryReprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogeneinduced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in

show abstract

“…DNA is restored to its original form by the action of replicative DNA polymerases and associated factors using the undamaged complementary strand as a template (14–16). Ataxia telangiectasia mutated and Rad3-related (ATR) is critical to UV DNA damage signaling (17,18), cell survival (19–22) and is linked with NER (23–25). We recently described a molecular pathway linking MC1R signaling with NER through a protein kinase A (PKA)-mediated phosphorylation event on ATR at S435, which accelerates XPA recruitment to sites of UV-induced DNA damage (5).…”

Section: Introductionmentioning

confidence: 99%

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Jarrett

Horrell

D’Orazio

2016

Nucleic Acids Research

View full text Add to dashboard Cite

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5′ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.

show abstract

ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1

Cited by 85 publications

References 52 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

Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Contact Info

Product

Resources

About