Polyadenylation/deadenylation/tumor suppressor factors regulate 3' end processing under different cellular conditions
Item
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Title
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Polyadenylation/deadenylation/tumor suppressor factors regulate 3' end processing under different cellular conditions
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Identifier
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d_2009_2013:573048cef6b3:10268
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identifier
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10440
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Creator
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Cevher, Murat Alper,
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Contributor
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Frida E. Kleiman
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Date
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2009
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Language
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English
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Publisher
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City University of New York.
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Subject
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Molecular biology | 3' processing | BARD1 | CstF | deadenylation | PARN | polyadenylation
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Abstract
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Under DNA damaging conditions the steady-state levels of cellular mRNAs change as a result of regulation of either or both their biosynthesis and turnover. mRNA 3' end cleavage, involved in the regulation of mRNA stability, is strongly but transiently inhibited upon UV treatment. This inhibition is mediated by both the formation of the BRCA1/BARD1/CstF complex and the proteasomal-mediated degradation of RNA polymerase II (RNAP II). As CstF-50 interacts with the tumor suppressor BARD1 to inhibit 3' processing and with RNAP II to activate 3' cleavage, it has been proposed that this cleavage factor plays a coordinating role in the DNA damage response.;BARD1 is modified by ATM kinase-dependent phosphorylation at the consensus site T734 upon UV treatment. Here we show that the T734A mutation abrogates the UVinduced BARD1/CstF complex formation; the UV-induced degradation of RNAP II and the UV-induced inhibition of 3' cleavage. Chromatin immunoprecipitation reactions revealed that BARD1, CstF and RNAP II, involved in the UV-induced inhibition of 3' cleavage, associate at sites of DNA damage. Together these results indicate that BARD1 with the 3' processing factor CstF play a role in the DNA damage response.;To further understand the role of CstF-50 in the DNA damage response; we analyzed other CstF-50 interactors and found that DNA damage not only induces the formation of the BARD1/CstF-50/poly(A) specific ribonuclease (PARN) complex but also the expression levels of PARN. Based on the nature of the factors, it is possible to hypothesize that the PARN/CstF-50/BARD1 interaction regulates mRNA turnover in different cellular responses. Consistent with this, the CstF-50/PARN/BARD1 complex plays a role in inhibition of 3' cleavage and activation of deadenylation upon DNA damage. CstF-50/BARD1 can revert the cap binding protein 80-mediated inhibition of PARN activity. Importantly, it is shown that PARN affects both polyadenylation and stability of different mRNA precursors, such as housekeeping genes and some clinically significant genes, under different cellular conditions. These studies indicate that the PARN/CstF/BARD1 complex plays a role in the regulation of gene expression upon DNA damage, representing an alternative mechanism to prevent the processing of premature terminated messengers and to control the expression of oncogenes and DNA repair factors.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
