Functional interaction between FOXO3a and ATM regulates DNA damage response

Tsai, Wen Bin; Chung, Young-Min; Takahashi, Yoko; Xu, Zhaohui; Hu, Mickey C.T.

doi:10.1038/ncb1709

Cited by 176 publications

(172 citation statements)

References 29 publications

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“…Note Added in Proof-While this manuscript was under review, a new report showing that Foxo3 directly interacts with ATM and regulates its activity in response to DNA damage was published (51). These findings further the link between Foxo3 and ATM.…”

Section: Foxo3 Is a Physiological Regulator Of Oxidative Stress Inmentioning

confidence: 84%

Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

Yalçın¹,

Zhang²,

Luciano³

et al. 2008

Journal of Biological Chemistry

229

287

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Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROSindependent modulations of ATM and p16INK4a and ROSmediated activation of p53/p21 CIP1/WAF1/Sdi1 tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.

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Section: Foxo3 Is a Physiological Regulator Of Oxidative Stress Inmentioning

confidence: 84%

Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

Yalçın¹,

Zhang²,

Luciano³

et al. 2008

Journal of Biological Chemistry

229

287

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“…Similarly, the lines between transcription factors and repair factors have become more blurred. Several other transcription factors, including ATF2, FOXO3a, NR4A, and Sp1, are also known to localize to DSBs and directly stimulate DNA repair and/or checkpoint signaling independently of transcription (Bhoumik et al 2005;Tsai et al 2008;Malewicz et al 2011;Beishline et al 2012;Velez-Cruz and Johnson 2012;Malewicz and Perlmann 2014). Like E2F1, these other transcription factors localize to DSBs independently of their DNA-binding domains, but it is unclear whether they recruit histone-modifying or remodeling enzymes to alter chromatin structure at DSBs.…”

Section: S29a/s29amentioning

confidence: 99%

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

et al. 2016

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The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.

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“…Both, FoxO3a and Aven have also been shown to be needed for ATM autophosphorylation and for the formation of nuclear foci at double strand breaks. 54,55 The third member of the PI3-K family, DNA-PK, becomes activated by direct binding to unprotected DNA ends, particularly when the two co-factors, Ku70 and Ku80 are present. 56 It is presently unclear, whether DNA-PK also needs further co-factors apart from Ku70 and Ku80, but in light of the high homology to the other two PI3-K family members, it is quite likely, that the activation of DNA-PK is more complex than hitherto known.…”

Section: Introductionmentioning

confidence: 99%

Regulation of p53: The next generation

Blattner¹

2008

Cell Cycle

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The p53 protein is one of the most important tumor suppressor proteins. The most prevailing property of this tumor suppressor protein is its activation in response to DNA damage which counteracts the propagation of genetic alterations to daughter cells under conditions that provoke mutagenesis. In response to DNA damage and some other kinds of cellular stress the turnover of p53 is reduced or completely switched-off, which leads to a strong increase in the amount of the p53 protein and subsequently to the implementation of cell cycle arrest and apoptosis. Although post-translational modifications of p53 certainly contribute to the activation of p53 under physiologic conditions, an increase in the amount of the protein e.g., after overexpression, is sufficient for p53's deadly activities. This makes this tumor suppressor protein an interesting target for cancer therapy. This article summarizes the most important principles for the regulation of p53, with a particular focus on recent findings. Furthermore, open questions and possible future directions shall be discussed.

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Functional interaction between FOXO3a and ATM regulates DNA damage response

Cited by 176 publications

References 29 publications

Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

Regulation of p53: The next generation

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