Chris Norbury | University of Oxford (original) (raw)

Papers by Chris Norbury

Research paper thumbnail of Structural plasticity of Cid1 provides a basis for its distributive RNA terminal uridylyl transferase activity

Nucleic acids research, Jan 20, 2015

Terminal uridylyl transferases (TUTs) are responsible for the post-transcriptional addition of ur... more Terminal uridylyl transferases (TUTs) are responsible for the post-transcriptional addition of uridyl residues to RNA 3' ends, leading in some cases to altered stability. The Schizosaccharomyces pombe TUT Cid1 is a model enzyme that has been characterized structurally at moderate resolution and provides insights into the larger and more complex mammalian TUTs, ZCCHC6 and ZCCHC11. Here, we report a higher resolution (1.74 Å) crystal structure of Cid1 that provides detailed evidence for uracil selection via the dynamic flipping of a single histidine residue. We also describe a novel closed conformation of the enzyme that may represent an intermediate stage in a proposed product ejection mechanism. The structural insights gained, combined with normal mode analysis and biochemical studies, demonstrate that the plasticity of Cid1, particularly about a hinge region (N164-N165), is essential for catalytic activity, and provide an explanation for its distributive uridylyl transferase ac...

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Research paper thumbnail of Structural basis for the activity of a cytoplasmic RNA terminal uridylyl transferase

Nature Structural & Molecular Biology, 2012

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Research paper thumbnail of Decapping is preceded by 3′ uridylation in a novel pathway of bulk mRNA turnover

Nature Structural & Molecular Biology, 2009

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Research paper thumbnail of Cid1, a Fission Yeast Protein Required for SM Checkpoint Control when DNA Polymerase d or ε Is Inactivated

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Research paper thumbnail of Efficient RNA Polyuridylation by Noncanonical Poly(A) Polymerases

Molecular and Cellular Biology, 2007

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Research paper thumbnail of Cytoplasmic RNA: a case of the tail wagging the dog

Nature Reviews Molecular Cell Biology, 2013

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Research paper thumbnail of Animal Cell Cycles and Their Control

Annual Review of Biochemistry, 1992

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Research paper thumbnail of Improved crystallization and diffraction of caffeine-induced death suppressor protein 1 (Cid1)

Acta Crystallographica Section F Structural Biology Communications, 2015

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Research paper thumbnail of Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+

Cell, 1988

In the fission yeast S. pombe, the Mr = 34 kd product of the cdc2+ gene (p34cdc2) is a protein ki... more In the fission yeast S. pombe, the Mr = 34 kd product of the cdc2+ gene (p34cdc2) is a protein kinase that controls entry into mitosis. In Xenopus oocytes and other cells, maturation-promoting factor (MPF) appears in late G2 phase and is able to cause entry into mitosis. Purified MPF consists of two major proteins of Mr approximately equal to 32 kd and 45 kd and expresses protein kinase activity. We report here that antibodies to S. pombe p34cdc2 are able to immunoblot and immunoprecipitate the approximately equal to 32 kd component of MPF from Xenopus eggs. The Mr approximately equal to 32 kd and 45 kd proteins exist as a complex that expresses protein kinase activity. These findings indicate that a Xenopus p34cdc2 homolog is present in purified MPF and suggest that p34cdc2 is a component of the control mechanism initiating mitosis generally in eukaryotic cells.

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Research paper thumbnail of Regional Specialization: The NEXT Big Thing in Nuclear RNA Turnover

Molecular Cell, 2011

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Research paper thumbnail of The Long and Short of MicroRNA

Cell, 2013

MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to ... more MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to silence many different mRNAs in a precise manner, miRNA stability and efficacy is controlled by highly developed regulatory pathways and fine-tuning mechanisms both affecting miRNA processing and altering mature miRNA target specificity.

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Research paper thumbnail of Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM

Trends in Biochemical Sciences, 1995

‘Checkpoint’ controls arrest the cell cycle after DNA damage, allowing repair to take place befor... more ‘Checkpoint’ controls arrest the cell cycle after DNA damage, allowing repair to take place before mutations can be perpetuated. In multicellular organisms, DNA damage can also induce apoptotic cell death, protecting the organism at the expense of the individual cell. How does a cell ‘choose’ between cycle arrest and death? Analysis of two human tumour suppressor proteins, p53 and the ATM (ataxia-telangiectasia mutated) gene product, may provide some answers.

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Research paper thumbnail of G1 checkpoint establishment in vivo during embryonic liver development

BMC developmental biology, 2014

The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage respons... more The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage response (DDR). During embryonic development, the characteristics of cell cycle and DNA damage checkpoint evolve from an extremely short G1 cell phase and lacking G1 checkpoint to lengthening G1 phase and the establishment of the G1 checkpoint. However, the regulatory mechanisms governing these transitions are not well understood. In this study, pregnant mice were exposed to ionizing radiation (IR) to induce DNA damage at different embryonic stages; the kinetics and mechanisms of the establishment of DNA damage-mediated G1 checkpoint in embryonic liver were investigated. We found that the G2 cell cycle arrest was the first response to DNA damage in early developmental stages. Starting at E13.5/E15.5, IR mediated inhibition of the G1 to S phase transition became evident. Concomitantly, IR induced the robust expression of p21 and suppressed Cdk2/cyclin E activity, which might involve in the initi...

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Research paper thumbnail of RNA decay via 3′ uridylation

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2013

The post-transcriptional addition of non-templated nucleotides to the 3&a... more The post-transcriptional addition of non-templated nucleotides to the 3' ends of RNA molecules can have a profound impact on their stability and biological function. Evidence accumulated over the past few decades has identified roles for polyadenylation in RNA stabilisation, degradation and, in the case of eukaryotic mRNAs, translational competence. By contrast, the biological significance of RNA 3' modification by uridylation has only recently started to become apparent. The evolutionary origin of eukaryotic RNA terminal uridyltransferases can be traced to an ancestral poly(A) polymerase. Here we review what is currently known about the biological roles of these enzymes, the ways in which their activity is regulated and the consequences of this covalent modification for the target RNA molecule, with a focus on those instances where uridylation has been found to contribute to RNA degradation. Roles for uridylation have been identified in the turnover of mRNAs, pre-microRNAs, piwi-interacting RNAs and the products of microRNA-directed mRNA cleavage; many mature microRNAs are also modified by uridylation, though the consequences in this case are currently less well understood. In the case of piwi-interacting RNAs, modification of the 3'-terminal nucleotide by the HEN1 methyltransferase blocks uridylation and so stabilises the small RNA. The extent to which other uridylation-dependent mechanisms of RNA decay are similarly regulated awaits further investigation. This article is part of a Special Issue entitled: RNA Decay mechanisms.

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Research paper thumbnail of Sequence of Crm1/exportin 1 mutant alleles reveals critical sites associated with multidrug resistance

Current Genetics, 2001

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Research paper thumbnail of Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

Breast cancer research : BCR, 2003

HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast can... more HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21WAFI/CIPI. We previously showed that higher levels of cytoplasmic p21WAFI/CIPI in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21WAFI/CIPI expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21WAFI/CIPI staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). HER-2 was e...

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Research paper thumbnail of Therapeutic Exploitation of Checkpoint Defects in Cancer Cells Lacking p53 Function

Cell Cycle, 2002

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Research paper thumbnail of Transcriptional Coactivator Cited2 Induces Bmi1 and Mel18 and Controls Fibroblast Proliferation via Ink4a/ARF

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Research paper thumbnail of Requirement for Schizosaccharomyces pombe Top3 in the maintenance of chromosome integrity

Journal of Cell Science, 2004

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Research paper thumbnail of Translation initiation and its deregulation during tumorigenesis

British Journal of Cancer, 2002

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Research paper thumbnail of Structural plasticity of Cid1 provides a basis for its distributive RNA terminal uridylyl transferase activity

Nucleic acids research, Jan 20, 2015

Terminal uridylyl transferases (TUTs) are responsible for the post-transcriptional addition of ur... more Terminal uridylyl transferases (TUTs) are responsible for the post-transcriptional addition of uridyl residues to RNA 3' ends, leading in some cases to altered stability. The Schizosaccharomyces pombe TUT Cid1 is a model enzyme that has been characterized structurally at moderate resolution and provides insights into the larger and more complex mammalian TUTs, ZCCHC6 and ZCCHC11. Here, we report a higher resolution (1.74 Å) crystal structure of Cid1 that provides detailed evidence for uracil selection via the dynamic flipping of a single histidine residue. We also describe a novel closed conformation of the enzyme that may represent an intermediate stage in a proposed product ejection mechanism. The structural insights gained, combined with normal mode analysis and biochemical studies, demonstrate that the plasticity of Cid1, particularly about a hinge region (N164-N165), is essential for catalytic activity, and provide an explanation for its distributive uridylyl transferase ac...

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Research paper thumbnail of Structural basis for the activity of a cytoplasmic RNA terminal uridylyl transferase

Nature Structural & Molecular Biology, 2012

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Research paper thumbnail of Decapping is preceded by 3′ uridylation in a novel pathway of bulk mRNA turnover

Nature Structural & Molecular Biology, 2009

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Research paper thumbnail of Cid1, a Fission Yeast Protein Required for SM Checkpoint Control when DNA Polymerase d or ε Is Inactivated

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Efficient RNA Polyuridylation by Noncanonical Poly(A) Polymerases

Molecular and Cellular Biology, 2007

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Research paper thumbnail of Cytoplasmic RNA: a case of the tail wagging the dog

Nature Reviews Molecular Cell Biology, 2013

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Research paper thumbnail of Animal Cell Cycles and Their Control

Annual Review of Biochemistry, 1992

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Research paper thumbnail of Improved crystallization and diffraction of caffeine-induced death suppressor protein 1 (Cid1)

Acta Crystallographica Section F Structural Biology Communications, 2015

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Research paper thumbnail of Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+

Cell, 1988

In the fission yeast S. pombe, the Mr = 34 kd product of the cdc2+ gene (p34cdc2) is a protein ki... more In the fission yeast S. pombe, the Mr = 34 kd product of the cdc2+ gene (p34cdc2) is a protein kinase that controls entry into mitosis. In Xenopus oocytes and other cells, maturation-promoting factor (MPF) appears in late G2 phase and is able to cause entry into mitosis. Purified MPF consists of two major proteins of Mr approximately equal to 32 kd and 45 kd and expresses protein kinase activity. We report here that antibodies to S. pombe p34cdc2 are able to immunoblot and immunoprecipitate the approximately equal to 32 kd component of MPF from Xenopus eggs. The Mr approximately equal to 32 kd and 45 kd proteins exist as a complex that expresses protein kinase activity. These findings indicate that a Xenopus p34cdc2 homolog is present in purified MPF and suggest that p34cdc2 is a component of the control mechanism initiating mitosis generally in eukaryotic cells.

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Research paper thumbnail of Regional Specialization: The NEXT Big Thing in Nuclear RNA Turnover

Molecular Cell, 2011

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Research paper thumbnail of The Long and Short of MicroRNA

Cell, 2013

MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to ... more MicroRNAs (miRNAs) are versatile regulators of gene expression in higher eukaryotes. In order to silence many different mRNAs in a precise manner, miRNA stability and efficacy is controlled by highly developed regulatory pathways and fine-tuning mechanisms both affecting miRNA processing and altering mature miRNA target specificity.

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Research paper thumbnail of Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM

Trends in Biochemical Sciences, 1995

‘Checkpoint’ controls arrest the cell cycle after DNA damage, allowing repair to take place befor... more ‘Checkpoint’ controls arrest the cell cycle after DNA damage, allowing repair to take place before mutations can be perpetuated. In multicellular organisms, DNA damage can also induce apoptotic cell death, protecting the organism at the expense of the individual cell. How does a cell ‘choose’ between cycle arrest and death? Analysis of two human tumour suppressor proteins, p53 and the ATM (ataxia-telangiectasia mutated) gene product, may provide some answers.

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Research paper thumbnail of G1 checkpoint establishment in vivo during embryonic liver development

BMC developmental biology, 2014

The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage respons... more The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage response (DDR). During embryonic development, the characteristics of cell cycle and DNA damage checkpoint evolve from an extremely short G1 cell phase and lacking G1 checkpoint to lengthening G1 phase and the establishment of the G1 checkpoint. However, the regulatory mechanisms governing these transitions are not well understood. In this study, pregnant mice were exposed to ionizing radiation (IR) to induce DNA damage at different embryonic stages; the kinetics and mechanisms of the establishment of DNA damage-mediated G1 checkpoint in embryonic liver were investigated. We found that the G2 cell cycle arrest was the first response to DNA damage in early developmental stages. Starting at E13.5/E15.5, IR mediated inhibition of the G1 to S phase transition became evident. Concomitantly, IR induced the robust expression of p21 and suppressed Cdk2/cyclin E activity, which might involve in the initi...

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Research paper thumbnail of RNA decay via 3′ uridylation

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2013

The post-transcriptional addition of non-templated nucleotides to the 3&a... more The post-transcriptional addition of non-templated nucleotides to the 3' ends of RNA molecules can have a profound impact on their stability and biological function. Evidence accumulated over the past few decades has identified roles for polyadenylation in RNA stabilisation, degradation and, in the case of eukaryotic mRNAs, translational competence. By contrast, the biological significance of RNA 3' modification by uridylation has only recently started to become apparent. The evolutionary origin of eukaryotic RNA terminal uridyltransferases can be traced to an ancestral poly(A) polymerase. Here we review what is currently known about the biological roles of these enzymes, the ways in which their activity is regulated and the consequences of this covalent modification for the target RNA molecule, with a focus on those instances where uridylation has been found to contribute to RNA degradation. Roles for uridylation have been identified in the turnover of mRNAs, pre-microRNAs, piwi-interacting RNAs and the products of microRNA-directed mRNA cleavage; many mature microRNAs are also modified by uridylation, though the consequences in this case are currently less well understood. In the case of piwi-interacting RNAs, modification of the 3'-terminal nucleotide by the HEN1 methyltransferase blocks uridylation and so stabilises the small RNA. The extent to which other uridylation-dependent mechanisms of RNA decay are similarly regulated awaits further investigation. This article is part of a Special Issue entitled: RNA Decay mechanisms.

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Research paper thumbnail of Sequence of Crm1/exportin 1 mutant alleles reveals critical sites associated with multidrug resistance

Current Genetics, 2001

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Research paper thumbnail of Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

Breast cancer research : BCR, 2003

HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast can... more HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21WAFI/CIPI. We previously showed that higher levels of cytoplasmic p21WAFI/CIPI in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21WAFI/CIPI expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21WAFI/CIPI staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). HER-2 was e...

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Research paper thumbnail of Therapeutic Exploitation of Checkpoint Defects in Cancer Cells Lacking p53 Function

Cell Cycle, 2002

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Research paper thumbnail of Transcriptional Coactivator Cited2 Induces Bmi1 and Mel18 and Controls Fibroblast Proliferation via Ink4a/ARF

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Requirement for Schizosaccharomyces pombe Top3 in the maintenance of chromosome integrity

Journal of Cell Science, 2004

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Research paper thumbnail of Translation initiation and its deregulation during tumorigenesis

British Journal of Cancer, 2002

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