Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1

Cai, Bin; Ju, Jeong Ho; Lee, Ji-Hoon; Paull, Tanya T.; Gelmann, Edward P.

doi:10.1016/j.celrep.2013.06.039

Cited by 35 publications

(53 citation statements)

References 49 publications

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“…With H 2 O 2 treatment, S85D/T86E, T372E/T373E and T86E/T373E mutants are all similar to WT ATM (Figure S5). In contrast to the in vitro result (Figure 4E), the T1985E/S1987D/S1988D ATM mutant could be normally activated by H 2 O 2 in cells (Figure S5B), possibly because of the action of other ATM stimulators such as ATMIN and NKX3.1 (Bowen et al, 2013; Kanu and Behrens, 2007). …”

Section: Resultscontrasting

confidence: 73%

Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

et al. 2017

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SUMMARY Ataxia-Telangiectasia Mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice.

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Section: Resultscontrasting

confidence: 73%

Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

et al. 2017

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“…NKX3.1 itself affects the DNA repair response by activating ATM kinase and ATM recruitment to sites of DNA damage (12). We hypothesized that NKX3.1 could affect TMPRSS2-ERG recombination not only by interacting with AR, but also by influencing the response to DNA damage that ensued from AR binding.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, NKX3.1 itself is involved in DNA repair. NKX3.1 enhances cell survival after DNA damage and migrates to sites of DNA damage to recruit DNA repair proteins and augment their activation (11, 12). NKX3.1 also binds to and activates topoisomerase I (13).…”

Section: Introductionmentioning

confidence: 99%

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

2015

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TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.

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“…These observations suggest the presence of a checkpoint barrier that inhibits PDB-driven genetic instability in non-malignant prostate epithelial tissue and is lost or attenuated in prostate cancer tissue. The checkpoint barrier is probably orchestrated by ATM, which is partially activated in prostate cancer cells 130 . Consistent with this, inactivation of ATM in the presence of androgen induces TMPRSS2-ERG fusion in non-malignant prostate epithelial cells 131 .…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

Atteya²,

2015

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The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.

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Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1

Cited by 35 publications

References 49 publications

Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

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