Ataxia Telangiectasia Mutated (ATM) Is Essential for DNA-PKcs Phosphorylations at the Thr-2609 Cluster upon DNA Double Strand Break

Chen, Benjamin P.C.; Uematsu, Naoya; Kobayashi, Junya; Lerenthal, Yaniv; Krempler, Andrea; Yajima, H.; Löbrich, Markus; Shiloh, Yosef; Chen, David J.

doi:10.1074/jbc.m611605200

Cited by 260 publications

(277 citation statements)

References 30 publications

(51 reference statements)

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“…With NU7026 treatment, phosphorylation at this site was undetectable in hTERT184-ATM5 cells. This indicates both ATM-dependent and DNA-PK-dependent contributions to Thr 2609 phosphorylation, consistent with previously published results showing that this particular residue can be phosphorylated by ATM and DNA-PK (16,17).…”

Section: Cancer Researchsupporting

confidence: 80%

“…This complementarity is strongly indicated by the observation that mice deficient in ATM and DNAPKcs are embryonic lethal (13). Additionally, there is some substrate redundancy in the kinase activities of DNA-PK and ATM, such as the phosphorylations of H2AX, replication protein A, and even DNA-PKcs itself after DNA damage (14)(15)(16)(17). However, in spite of these observations, the extent of functional overlap between ATM and DNA-PK and whether DNA-PK plays a role in cell cycle checkpoint functions remain unclear.…”

Section: Introductionmentioning

confidence: 98%

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DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells

Arlander

Greene²,

Innes³

et al. 2008

Cancer Research

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Section: Cancer Researchsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 98%

DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells

Arlander

Greene²,

Innes³

et al. 2008

Cancer Research

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“…Cell Culture-HEK293 cells expressing wild-type and 6A DNAPKcs (T2609A/S2612A/T2620A/S2624A/T2638A/T2647A) (26) (provided by Dr. David Chen) and ER-AsiSI U2OS cells (provided by Dr. Gaëlle Legube) were grown in Dulbecco's modified Eagle's medium (Invitrogen) containing 10% fetal bovine serum (FBS) (Invitrogen). 293-6E cells were provided by Dr. Yves Durocher and were grown in F17 medium (Invitrogen) supplemented with 4 mM L-Glutamine and 0.1% pluronic F-68 (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

DNA-dependent Protein Kinase Regulates DNA End Resection in Concert with Mre11-Rad50-Nbs1 (MRN) and Ataxia Telangiectasia-mutated (ATM)

Zhou

Paull

2013

Journal of Biological Chemistry

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Background:The processing of DNA double strand breaks is critical for homologous recombination. Results: The nonhomologous end joining factor DNA-dependent protein kinase (DNA-PK) blocks end resection but is regulated by autophosphorylation, the Mre11-Rad5-Nbs1 (MRN) complex, and the ataxia telangiectasia-mutated (ATM) kinase. Conclusion: DNA-PK regulates DNA end processing for homologous recombination. Significance: Analyzing the effects of NHEJ factors on end processing is essential to our understanding of homologous recombination.

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“…Because SMC3 is phosphorylated by the ATM kinase, the effect of ATM on SMC3 binding at cohesion sites was investigated in HeLa cells in which ATM is stably knocked down by a short hairpin RNA (36). ATM knockdown caused an ϳ50% decrease of pS1083-SMC3 binding at cohesin sites compared with that in the control knockdown (Fig.…”

Section: Phosphorylated Smc1/3 Binds Cohesion Sites In An Atm-dependentmentioning

confidence: 99%

Genome-wide Reinforcement of Cohesin Binding at Pre-existing Cohesin Sites in Response to Ionizing Radiation in Human Cells

Kim

Zhang

et al. 2010

Journal of Biological Chemistry

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The cohesin complex plays a central role in genome maintenance by regulation of chromosome segregation in mitosis and DNA damage response (DDR) in other phases of the cell cycle. The ATM/ATR phosphorylates SMC1 and SMC3, two core components of the cohesin complex to regulate checkpoint signaling and DNA repair. In this report, we show that the genomewide binding of SMC1 and SMC3 after ionizing radiation (IR) is enhanced by reinforcing pre-existing cohesin binding sites in human cancer cells. We demonstrate that ATM and SMC3 phosphorylation at Ser 1083 regulate this process. We also demonstrate that acetylation of SMC3 at Lys 105 and Lys 106 is induced by IR and this induction depends on the acetyltransferase ESCO1 as well as the ATM/ATR kinases. Consistently, both ESCO1 and SMC3 acetylation are required for intra-S phase checkpoint and cellular survival after IR. Although both IR-induced acetylation and phosphorylation of SMC3 are under the control of ATM/ATR, the two forms of modification are independent of each other and both are required to promote reinforcement of SMC3 binding to cohesin sites. Thus, SMC3 modifications is a mechanism for genome-wide reinforcement of cohesin binding in response to DNA damage response in human cells and enhanced cohesion is a downstream event of DDR.Sister chromatid cohesion is a fundamental biological process that the sister chromatids once generated in S-phase are always paired and linked to ensure equal distribution to daughter cells until mitosis. Cohesion plays a central role in genome stability by facilitating spindle bi-orientation, faithful chromosome segregation, homologous recombination, checkpoint activation, and transcriptional regulation (1-3). This process is mediated by a protein complex called cohesin that consists of four core subunits SMC1, SMC3, RAD21 (also known as SCC1 and MCD1), and SA2/SA1 (also known as SCC3, or STAG2 and STAG1) and several accessory factors (4).To maintain the fidelity of the genome, cells evolve with an elaborate mechanism to deal with DNA damage. DNA damage response (DDR) 3 is a signal transduction pathway that coordinates cell cycle arrest, DNA repair, and programmed cell death in the presence of damaged DNA (5, 6). It is regulated by the ATM/ATR, master regulators of the DDR process through phosphorylation of their substrates (6 -10). Disruption of DDR results in genomic instability and is the cause for many cancerprone disorders (11). Cohesin is an important effector in the DNA damage response. SMC1 and SMC3 are phosphorylated in human and mouse cells in an ATM/ATR-dependent manner and these phosphorylation events are required for intra-S checkpoint, cellular survival in response to IR (12-15). Cohesin is recruited to sites of DNA damage for efficient DNA repair (4,12,16,17). However, the molecular mechanism by which cohesin phosphorylation regulates DDR is still unknown.Acetylation is another post-translational modification mechanism for the regulation of cohesin functions. It has been long recognized that Eco1 (establishment o...

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Ataxia Telangiectasia Mutated (ATM) Is Essential for DNA-PKcs Phosphorylations at the Thr-2609 Cluster upon DNA Double Strand Break

Cited by 260 publications

References 30 publications

DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells

DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells

DNA-dependent Protein Kinase Regulates DNA End Resection in Concert with Mre11-Rad50-Nbs1 (MRN) and Ataxia Telangiectasia-mutated (ATM)

Genome-wide Reinforcement of Cohesin Binding at Pre-existing Cohesin Sites in Response to Ionizing Radiation in Human Cells

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