Modified and unmodified PSM counts for each AA position with a C-terminal +129 Da modification ac... more Modified and unmodified PSM counts for each AA position with a C-terminal +129 Da modification across all timepoints. The plots show unmodified (green) and +129 Da modified (purple) PSM counts across all nine timepoints (x-axis) for the C-terminal position of the two proteins that have at least one PSM identified by MODa as containing a C-terminal +129 Da modification. Counts represent the average of the three biologcial replicates. (PDF 14 kb)
Zip file containing several data tables in tab-separated format, as well as a readme file that ex... more Zip file containing several data tables in tab-separated format, as well as a readme file that explains the contents of each data file. (ZIP 175 kb)
Modified and unmodified counts across timepoints for the top 15 exponential-enriched AA positions... more Modified and unmodified counts across timepoints for the top 15 exponential-enriched AA positions with a +16 Da modification to tryptophan. The plots show unmodified (green) and +16 Da modified (orange) tryptophan PSM counts across all nine timepoints (x-axis) for the protein and position indicated. Plots in columns correspond to the three biological replicates 1 (left column), 2 (center column), and 3 (right column). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text), with the most significant protein at the top. (PDF 25 kb)
Modified and unmodified counts across timepoints for the top 10 exponential-enriched AA positions... more Modified and unmodified counts across timepoints for the top 10 exponential-enriched AA positions with a +16 Da modification to methionine. The plots show unmodified (green) and +16 Da modified (magenta) methionine PSM counts across all nine timepoints (x-axis) for the protein and position indicated. Plots in columns correspond to the three biological replicates 1 (left column), 2 (center column), and 3 (right column). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text), with the most significant protein at the top. (PDF 25 kb)
Amino Acid sequence logos generated using WebLogo [92] for a +/- 5 AA window around the MODa-call... more Amino Acid sequence logos generated using WebLogo [92] for a +/- 5 AA window around the MODa-called site of modification for the top 50 most abundant +1Da modifications localized at Asparagine residues (A) and at all other residue types combined (B). Asparagine residues show a preferential enrichment of Glycine, Serine, and Asparagine AAs at the +1 position not observed for non-Asn modifications. (PDF 347 kb)
Modified and unmodified PSM counts for each AA position with a significantly stationary-phase bia... more Modified and unmodified PSM counts for each AA position with a significantly stationary-phase biased +1 Da modification to asparagine. The plots show unmodified (green) and +1 Da modified (brown) PSM counts across all nine timepoints (x-axis) for the 10 asparagine residues with the most significant p-values across all three biological replicates. Counts represent the average of the three biologcial replicates. Plots are ordered by the mean p value of the Fisherâ s exact test for preferential modification from left-to-right within each row, and from top-to-bottom across rows, with the most significant position at the top left. (PDF 20 kb)
Fraction of total peptides across timepoints with an N-terminal alanine possessing a +42 Da modif... more Fraction of total peptides across timepoints with an N-terminal alanine possessing a +42 Da modification. The plots show unmodified (green) and +42 Da modified (blue) PSM counts across all nine timepoints (x-axis) for the N-terminal position of all proteins that have both (i) at least one PSM identified by MODa as containing an N-terminal +42 Da modification and (ii) having a penultimate Alanine (AA position 2; i.e. the N-terminal residue following N-terminal methionine cleavage). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text) from top to bottom, with the most significant protein at the top. (PDF 17 kb)
Temporally variable modification for individual proteins with an N-terminal threonine possessing ... more Temporally variable modification for individual proteins with an N-terminal threonine possessing a +42 Da modification. The plots show unmodified (green) and +42 Da Modified (blue) PSM counts across all nine timepoints (x-axis) for the N-terminal position of all proteins that have both (i) at least one PSM identified by MODa as containing an N-terminal +42 Da modification and (ii) having a penultimate threonine (AA position 2; i.e. the N-terminal residue following N-terminal methionine cleavage). Counts represent the average of the three biological replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text) from top to bottom, with the most significant protein at the top. (PDF 17 kb)
Modified and unmodified counts across timepoints for all AA positions with a +16 Da modification ... more Modified and unmodified counts across timepoints for all AA positions with a +16 Da modification to methionine, pooled by biological replicate. The plots show the total unmodified (green) and +16 Da modified (magenta) PSM counts across all nine timepoints (x-axis) for methionine residues that have at least one +16 Da modification at any time point in any replicate. The three panels show counts for each of the three biological replicates, replicate 1 (A), replicate 2 (B) and replicate 3 (C). Note that the y-axis is plotted on a logarithmic (base 10) scale due to the high number of total counts relative to modified counts. (PDF 16 kb)
To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maint... more To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maintenance. One unsolved problem is the mechanism of regulation of DNA double-strand break repair by REV7 in complex with 53BP1 and RIF1, and its influence on repair pathway choice between homologous recombination and non-homologous end-joining. We searched for REV7-associated factors in human cells and found FAM35A, a previously unstudied protein with an unstructured N-terminal region and a C-terminal region harboring three OB-fold domains similar to single-stranded DNA-binding protein RPA, as novel interactor of REV7/RIF1/53BP1. FAM35A re-localized in damaged cell nuclei, and its knockdown caused sensitivity to DNA-damaging agents. In a BRCA1-mutant cell line, however, depletion of FAM35A increased resistance to camptothecin, suggesting that FAM35A participates in processing of DNA ends to allow more efficient DNA repair. We found FAM35A absent in one widely used BRCA1-mutant cancer cell l...
Advances in experimental medicine and biology, 2016
An increasing number of web resources are available for aiding in proteomics research. Databases ... more An increasing number of web resources are available for aiding in proteomics research. Databases contain repositories of proteins and associated information. A recent article by Chen et al. (Genomics Proteomics Bioinformatics 13(1):36-39, 2015) evaluates a number of MS-based proteomics repositories containing MS and expression data, including repositories devoted to cataloguing high confidence post-translational modifications. Many sites have tools developed by research labs that are shared with the community and online tutorials and videos for learning how to use the tools. This chapter contains a selection of web sites useful for proteomics analyses but is by no means comprehensive. Using a search engine such as Google is the easiest way to find the sites using the name given below.
The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several type... more The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We find that both GLI3 and GLI1 bind to the pluripotency factor NANOG. The ectopic expression of NANOG inhibits GLI1-mediated transcriptional responses in a dose-dependent fashion. In differentiating ES cells, the presence of NANOG reduces the transcriptional response of cells to HH. Finally, we find that Gli1 and Nanog are co-expressed in ES cells at high levels. We propose that NANOG acts as a negative feedback component that provides stem cell-specific regulation of the HH pathway.
The molecular mechanisms underlying excessive alcohol consumption are not fully understood. Sever... more The molecular mechanisms underlying excessive alcohol consumption are not fully understood. Several recent reports from the Integrative Neuroscience Initiative on Alcoholism (INIA) consortium show that alcohol administration induces changes in the expression levels of a number of genes involved in synaptic transmission. These changes likely affect the expression levels of the corresponding proteins, which in turn, alter their ability to establish protein-protein interactions required for normal regulation of brain function. Thus, we hypothesize that clusters of genes that change in response to alcohol perturbation may predict protein complexes that underlie alcohol-related phenotypes. In order to better understand the cellular and molecular events that could contribute to alcohol dependence in mice, the objective of our study was to first identify novel protein complexes of key brain signaling systems and, then, to determine the effect of excessive alcohol consumption on the identif...
The Journal of nutritional biochemistry, Jan 12, 2014
Elevated homocysteine levels have long been associated with various disease states, including car... more Elevated homocysteine levels have long been associated with various disease states, including cardiovascular disease and birth defects, including neural tube defects (NTDs). One hypothesis regarding the strong correlation between these various disorders and high levels of homocysteine is that a reactive form of this small molecule can attach to mammalian proteins in a phenomenon known as homocysteinylation. These posttranslational modifications may become antigenic or may even directly disrupt certain protein function. It remains to be determined whether dietary influences that can cause globally increased levels of circulating homocysteine confer negative effects maternally, or may otherwise negatively and materially impact the metabolic balance in developing embryos. Herein we present the application of a chemical method of determination of N-homocysteinylation to a set of neural tube closure stage mouse embryos and their mothers. We explore the uses of this newly described techni...
We previously reported a protein expression profiling experiment conducted on human pancreatic ti... more We previously reported a protein expression profiling experiment conducted on human pancreatic tissues using 2D gel electrophoresis and mass spectrometry. Here, 18 spots that were identified in the gel at molecular weights more than 10 kDa lower than ...
Proceedings of the National Academy of Sciences, 2010
Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle w... more Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm -deficient mic...
Modified and unmodified PSM counts for each AA position with a C-terminal +129 Da modification ac... more Modified and unmodified PSM counts for each AA position with a C-terminal +129 Da modification across all timepoints. The plots show unmodified (green) and +129 Da modified (purple) PSM counts across all nine timepoints (x-axis) for the C-terminal position of the two proteins that have at least one PSM identified by MODa as containing a C-terminal +129 Da modification. Counts represent the average of the three biologcial replicates. (PDF 14 kb)
Zip file containing several data tables in tab-separated format, as well as a readme file that ex... more Zip file containing several data tables in tab-separated format, as well as a readme file that explains the contents of each data file. (ZIP 175 kb)
Modified and unmodified counts across timepoints for the top 15 exponential-enriched AA positions... more Modified and unmodified counts across timepoints for the top 15 exponential-enriched AA positions with a +16 Da modification to tryptophan. The plots show unmodified (green) and +16 Da modified (orange) tryptophan PSM counts across all nine timepoints (x-axis) for the protein and position indicated. Plots in columns correspond to the three biological replicates 1 (left column), 2 (center column), and 3 (right column). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text), with the most significant protein at the top. (PDF 25 kb)
Modified and unmodified counts across timepoints for the top 10 exponential-enriched AA positions... more Modified and unmodified counts across timepoints for the top 10 exponential-enriched AA positions with a +16 Da modification to methionine. The plots show unmodified (green) and +16 Da modified (magenta) methionine PSM counts across all nine timepoints (x-axis) for the protein and position indicated. Plots in columns correspond to the three biological replicates 1 (left column), 2 (center column), and 3 (right column). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text), with the most significant protein at the top. (PDF 25 kb)
Amino Acid sequence logos generated using WebLogo [92] for a +/- 5 AA window around the MODa-call... more Amino Acid sequence logos generated using WebLogo [92] for a +/- 5 AA window around the MODa-called site of modification for the top 50 most abundant +1Da modifications localized at Asparagine residues (A) and at all other residue types combined (B). Asparagine residues show a preferential enrichment of Glycine, Serine, and Asparagine AAs at the +1 position not observed for non-Asn modifications. (PDF 347 kb)
Modified and unmodified PSM counts for each AA position with a significantly stationary-phase bia... more Modified and unmodified PSM counts for each AA position with a significantly stationary-phase biased +1 Da modification to asparagine. The plots show unmodified (green) and +1 Da modified (brown) PSM counts across all nine timepoints (x-axis) for the 10 asparagine residues with the most significant p-values across all three biological replicates. Counts represent the average of the three biologcial replicates. Plots are ordered by the mean p value of the Fisherâ s exact test for preferential modification from left-to-right within each row, and from top-to-bottom across rows, with the most significant position at the top left. (PDF 20 kb)
Fraction of total peptides across timepoints with an N-terminal alanine possessing a +42 Da modif... more Fraction of total peptides across timepoints with an N-terminal alanine possessing a +42 Da modification. The plots show unmodified (green) and +42 Da modified (blue) PSM counts across all nine timepoints (x-axis) for the N-terminal position of all proteins that have both (i) at least one PSM identified by MODa as containing an N-terminal +42 Da modification and (ii) having a penultimate Alanine (AA position 2; i.e. the N-terminal residue following N-terminal methionine cleavage). Counts represent the average of the three biologcial replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text) from top to bottom, with the most significant protein at the top. (PDF 17 kb)
Temporally variable modification for individual proteins with an N-terminal threonine possessing ... more Temporally variable modification for individual proteins with an N-terminal threonine possessing a +42 Da modification. The plots show unmodified (green) and +42 Da Modified (blue) PSM counts across all nine timepoints (x-axis) for the N-terminal position of all proteins that have both (i) at least one PSM identified by MODa as containing an N-terminal +42 Da modification and (ii) having a penultimate threonine (AA position 2; i.e. the N-terminal residue following N-terminal methionine cleavage). Counts represent the average of the three biological replicates. Plots are ordered from top to bottom by the mean p value of the Fisherâ s exact test for preferential modification (see text) from top to bottom, with the most significant protein at the top. (PDF 17 kb)
Modified and unmodified counts across timepoints for all AA positions with a +16 Da modification ... more Modified and unmodified counts across timepoints for all AA positions with a +16 Da modification to methionine, pooled by biological replicate. The plots show the total unmodified (green) and +16 Da modified (magenta) PSM counts across all nine timepoints (x-axis) for methionine residues that have at least one +16 Da modification at any time point in any replicate. The three panels show counts for each of the three biological replicates, replicate 1 (A), replicate 2 (B) and replicate 3 (C). Note that the y-axis is plotted on a logarithmic (base 10) scale due to the high number of total counts relative to modified counts. (PDF 16 kb)
To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maint... more To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maintenance. One unsolved problem is the mechanism of regulation of DNA double-strand break repair by REV7 in complex with 53BP1 and RIF1, and its influence on repair pathway choice between homologous recombination and non-homologous end-joining. We searched for REV7-associated factors in human cells and found FAM35A, a previously unstudied protein with an unstructured N-terminal region and a C-terminal region harboring three OB-fold domains similar to single-stranded DNA-binding protein RPA, as novel interactor of REV7/RIF1/53BP1. FAM35A re-localized in damaged cell nuclei, and its knockdown caused sensitivity to DNA-damaging agents. In a BRCA1-mutant cell line, however, depletion of FAM35A increased resistance to camptothecin, suggesting that FAM35A participates in processing of DNA ends to allow more efficient DNA repair. We found FAM35A absent in one widely used BRCA1-mutant cancer cell l...
Advances in experimental medicine and biology, 2016
An increasing number of web resources are available for aiding in proteomics research. Databases ... more An increasing number of web resources are available for aiding in proteomics research. Databases contain repositories of proteins and associated information. A recent article by Chen et al. (Genomics Proteomics Bioinformatics 13(1):36-39, 2015) evaluates a number of MS-based proteomics repositories containing MS and expression data, including repositories devoted to cataloguing high confidence post-translational modifications. Many sites have tools developed by research labs that are shared with the community and online tutorials and videos for learning how to use the tools. This chapter contains a selection of web sites useful for proteomics analyses but is by no means comprehensive. Using a search engine such as Google is the easiest way to find the sites using the name given below.
The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several type... more The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We find that both GLI3 and GLI1 bind to the pluripotency factor NANOG. The ectopic expression of NANOG inhibits GLI1-mediated transcriptional responses in a dose-dependent fashion. In differentiating ES cells, the presence of NANOG reduces the transcriptional response of cells to HH. Finally, we find that Gli1 and Nanog are co-expressed in ES cells at high levels. We propose that NANOG acts as a negative feedback component that provides stem cell-specific regulation of the HH pathway.
The molecular mechanisms underlying excessive alcohol consumption are not fully understood. Sever... more The molecular mechanisms underlying excessive alcohol consumption are not fully understood. Several recent reports from the Integrative Neuroscience Initiative on Alcoholism (INIA) consortium show that alcohol administration induces changes in the expression levels of a number of genes involved in synaptic transmission. These changes likely affect the expression levels of the corresponding proteins, which in turn, alter their ability to establish protein-protein interactions required for normal regulation of brain function. Thus, we hypothesize that clusters of genes that change in response to alcohol perturbation may predict protein complexes that underlie alcohol-related phenotypes. In order to better understand the cellular and molecular events that could contribute to alcohol dependence in mice, the objective of our study was to first identify novel protein complexes of key brain signaling systems and, then, to determine the effect of excessive alcohol consumption on the identif...
The Journal of nutritional biochemistry, Jan 12, 2014
Elevated homocysteine levels have long been associated with various disease states, including car... more Elevated homocysteine levels have long been associated with various disease states, including cardiovascular disease and birth defects, including neural tube defects (NTDs). One hypothesis regarding the strong correlation between these various disorders and high levels of homocysteine is that a reactive form of this small molecule can attach to mammalian proteins in a phenomenon known as homocysteinylation. These posttranslational modifications may become antigenic or may even directly disrupt certain protein function. It remains to be determined whether dietary influences that can cause globally increased levels of circulating homocysteine confer negative effects maternally, or may otherwise negatively and materially impact the metabolic balance in developing embryos. Herein we present the application of a chemical method of determination of N-homocysteinylation to a set of neural tube closure stage mouse embryos and their mothers. We explore the uses of this newly described techni...
We previously reported a protein expression profiling experiment conducted on human pancreatic ti... more We previously reported a protein expression profiling experiment conducted on human pancreatic tissues using 2D gel electrophoresis and mass spectrometry. Here, 18 spots that were identified in the gel at molecular weights more than 10 kDa lower than ...
Proceedings of the National Academy of Sciences, 2010
Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle w... more Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm -deficient mic...
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