Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation

Ali, Ambereen; Zhang, Ji; Bao, Shideng; Liu, Irene; Otterness, Diane M.; Dean, Nicholas M.; Abraham, Robert T.; Wang, Xiao Fan

doi:10.1101/gad.1176004

Cited by 154 publications

(156 citation statements)

References 29 publications

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“…Disruption of PP5 activity by siRNA resulted in defects in ATM activation and radioresistant DNA synthesis. In addition, the phosphatase activity of PP5 was shown to be required for ATM autophosphorylation and activation (Ali et al, 2004). These findings suggest that PP5 might control ATM kinase activity by dephosphorylating ATM, the MRN complex, or other factors involved in ATM activation.…”

Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 88%

“…Recent articles show that two phosphatases, protein phosphatase 2A (PP2A) and protein phosphatase 5 (PP5), both affect ATM activity in vivo (Ali et al, 2004;Goodarzi et al, 2004). PP2A is a member of the protein serine/threonine phosphatase family and is composed of a catalytic (C) subunit, a scaffolding A subunit and a regulatory B subunit.…”

Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 99%

“…Ali et al (2004) showed that PP5 coimmunoprecipitates with ATM from human cells, but unlike PP2A, this interaction increases after exposure to either NCS or IR. Disruption of PP5 activity by siRNA resulted in defects in ATM activation and radioresistant DNA synthesis.…”

Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 99%

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Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 88%

Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 99%

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Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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“…What is not clear yet is whether ATM pS367 and pS1893 coincide with pS1981 at the break site or whether they are associated with movement of ATM from the site to the flanking regions. Not surprisingly, protein phosphatases have also been shown to play a role in ATM activation (Ali et al, 2004;Goodarzi et al, 2004). DNA-damaged-induced acetylation of ATM has been reported by Sun et al (2005) and this was shown to run in parallel with pS1981 after radiation exposure.…”

Section: Perspectivementioning

confidence: 95%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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“…Earlier studies have shown a role for PP5 in the activation of cell cycle checkpoints in response to DSBs. Thus, MEFs from PP5 deficient mice exhibit a reduction in ATM activation subsequent to DSBs and an alteration in the G2/M checkpoint (Ali et al, 2004). In this context a role for PP5 in the activation of PARP-1 is aligned with a role for PP5 in the activation of ATM.…”

Section: Discussionmentioning

confidence: 94%

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Fang¹,

Soubeyrand²,

Haché

2010

Oncogene

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Poly (ADP-ribose) polymerase-1 (PARP-1) has an important role in the cellular response to a broad spectrum of DNA lesions. PARP-1 is strongly activated in response to double-stranded DNA breaks (DSBs), yet its contribution to the DSB response is poorly understood. Here we used bleomycin, a radiomimetic that generates DSBs with high specificity to focus on the response of PARP-1 to DSBs. We report that the induction of PARP-1 activity by bleomycin depends on the Ku antigen, a nonhomologous-DNA-End-Joining factor and protein phosphatase 5 (PP5). PARP-1 activation in response to bleomycin was reduced over 10-fold in Ku-deficient cells, whereas its activation in response to U.V. was unaffected. PARP-1 activation was rescued by reexpression of Ku, but was refractory to manipulation of DNA-dependent protein kinase or ATM. Similarly, PARP-1 activation subsequent to bleomycin was reduced 2-fold on ablation of PP5 and was increased 5-fold when PP5 was overexpressed. PP5 seemed to act directly on PARP-1, as its basal phosphorylation was reduced on overexpression of PP5, and PP5 dephosphorylated PARP-1 in vitro. These results highlight the functional importance of Ku antigen and PP5 for PARP-1 activity subsequent to DSBs.

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Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation

Cited by 154 publications

References 29 publications

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

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