کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10919724 | 1090838 | 2011 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
ATM-dependent phosphorylation of 53BP1 in response to genomic stress in oxic and hypoxic cells
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
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چکیده انگلیسی
The ATM kinase is activated by chromatin modification following exogenous and endogenous DSBs or cell stress, including acute anoxia. The p53 binding protein 1 (53BP1) contains multiple ATM-consensus phosphorylation sites in its N- and C-termini and may therefore be a distal read-out of ATM function. We have examined the cellular activation of these phosphorylation sites for the first time in situ following anoxic/hypoxic stress and IR-induced exogenous DSBs. We show that multiple residues of 53BP1 are phosphorylated and that these phosphoforms form discrete nuclear foci following IR or during DNA replication as exogenous or endogenous DNA double strand breaks (DSBs), respectively. Novel data pertaining to the phosphorylation of 53BP1Ser25in situ supports its dependency on the ATM kinase; but this occurs independently of p53 function. We show that 53BP1Ser25 is activated specifically in S-phase cells during anoxia in an ATM-dependent manner. Exogenous DSBs form discrete IR-induced foci whereas oxygen stress induced non-localized 53BP1Ser25 activation. Our in vitro data are supported by irradiated xenograft studies in vivo whereby 53BP1Ser25 phosphorylation does not occur in sub-regions positive for the hypoxia marker EF5. We propose a model whereby DSBs induce chromatin modification at sites of DNA damage which are tracked by the ATM substrates γ H2AX and 53BP1Ser25 in a mechanism distinct from p53-mediated cell cycle arrest. Together this work indicates 53BP1Ser25, and possibly other 53BP1 phosphoforms, as a bona fide DSB-biomarkers for surveying ongoing DNA-damage related signaling in oxic and hypoxic cells during clinical radiotherapy.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Radiotherapy and Oncology - Volume 99, Issue 3, June 2011, Pages 307-312
Journal: Radiotherapy and Oncology - Volume 99, Issue 3, June 2011, Pages 307-312
نویسندگان
Shane M. Harding, Carla Coackley, Robert G. Bristow,