Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

Yamamoto, Kenta; Wang, Yunyue; Jiang, Wenxia; Liu, Xiangyu; Dubois, Richard L.; Lin, Chyuan‐Sheng; Ludwig, Thomas; Bakkenist, Christopher J.; Zha, Shan

doi:10.1083/jcb.201204098

Cited by 102 publications

(104 citation statements)

References 52 publications

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“…Previous ATM kinase inhibitor studies described DNA repair defects in cells that are not observed in ATM-null cells, suggesting that even the inactivated protein has roles in DNA repair (56,57). This was supported by two recent publications showing that the presence of full-length, kinase-dead ATM results in early embryonic lethality in mouse models (58,59). The enzymatically inactive ATM lacks dominant-negative interfering activity and yet interferes with homologous recombination to a greater extent than seen in ATM-null cells.…”

Section: Discussionsupporting

confidence: 69%

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Edwards

Helmus

Koeller

et al. 2013

J Virol

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A highly reproducible quantitative PCR (Q-PCR) assay was used to study the stability of human papillomavirus (HPV) in undifferentiated keratinocytes that maintain viral episomes. The term "stability" refers to the ability of episomes to persist with little copy number variation in cells. In investigating the mechanism of action of PA25, a previously published compound that destabilizes HPV episomes, aphidicolin was also found to markedly decrease episome levels, but via a different pathway from that of PA25. Since aphidicolin is known to activate DNA damage response (DDR) pathways, effects of inhibitors and small interfering RNAs (siRNAs) acting within DDR pathways were investigated. Inhibitors of Chk1 and siRNA directed against ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia Rad3-related (ATR) pathways significantly reduced viral episomes, suggesting that these pathways play a role in maintaining HPV episome stability. Inhibitors of Chk2 and DNA-PK had no effect on episome levels. Pharmacological inhibition of ATM proteins had no effect on episome levels, but ATM knockdown by siRNA significantly reduced episome levels, suggesting that ATM proteins are playing an important role in HPV episome stability that does not require kinase activity. These results outline two pathways that trigger episome loss from cells and suggest the existence of a littleunderstood mechanism that mediates viral DNA elimination. Together, our results also indicate that HPV episomes have a stability profile that is remarkably similar to that of fragile sites; these similarities are outlined and discussed. This close correspondence may influence the preference of HPV for integration into fragile sites.

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Section: Discussionsupporting

confidence: 69%

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Edwards

Helmus

Koeller

et al. 2013

J Virol

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“…1, C and D), indicating that a portion of HR reduction may be specific to ATM kinase inactivation by the inhibitors. It is possible that catalytically inactive ATM may interfere with HR as proposed recently (19,20,37,38) Fig. 2A), suggesting that ATM is dispensable for HR, including that controlled by ␥-H2AX.…”

Section: H2axmentioning

confidence: 99%

“…2) Because poly(ADP-ribose) polymerase (PARP) inhibition selectively kill cells defective for HR (16), synthetic lethality caused by combined deficiency of ATM and PARP1 or PARP2 may be due to synergistic impacts on ATMdependent HR and repair function of PARP1/2 (17,18). In fact, cells carrying homozygous ATM kinase-dead mutations display HR defects and elevated sensitivity to PARP inhibition (19,20).…”

mentioning

confidence: 99%

Ataxia Telangiectasia Mutated (ATM) Is Dispensable for Endonuclease I-SceI-induced Homologous Recombination in Mouse Embryonic Stem Cells

Rass

Chandramouly

Zha

et al. 2013

Journal of Biological Chemistry

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Background: ATM acts as a master controller of the DSB response by phosphorylating numerous DSB response proteins, some of which, including histone H2AX, function in homologous recombination (HR). Results: HR is not impaired in mouse ATM-null ES cells. Conclusion: ATM is dispensable for HR, including H2AX-dependent HR.Significance: This study helps clarify the perception that ATM has a general role in HR, including that controlled by H2AX.

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“…In addition to this rationale, there is precedent for pharmacologic inhibition of such kinases that can be extrapolated from animal studies where a defective kinase is more detrimental to the animal than a nonexpressed kinase. For instance, ATM knockout mice are viable and recapitulate A-T syndrome, whereas mutated "kinase dead" ATM results in embryonic lethality (65). Kinase inhibitors may have effects similar to the kinase-dead mutants; they not only inactivate the kinase target, but also leave the catalytically inactive kinase to block access to site of DNA damage from other proteins that would initiate alternative repair pathways.…”

Section: Therapeutic Opportunities In Atmdeficient Cancers: Inducing mentioning

confidence: 99%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

362

318

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Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states.

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Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

Abstract: Expression of a kinase-deficient ATM protein leads to severe genomic instability and embryonic lethality.

Cited by 102 publications

References 52 publications

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Ataxia Telangiectasia Mutated (ATM) Is Dispensable for Endonuclease I-SceI-induced Homologous Recombination in Mouse Embryonic Stem Cells

ATM Mutations in Cancer: Therapeutic Implications

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