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Systematic Analysis of the Genetic Variability That Impacts SUMO Conjugation and Their Involvement in Human Diseases.

Xu HD, Shi SP, Chen X, Qiu JD - Sci Rep (2015)

Bottom Line: Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs.We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system.More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Nanchang University, Nanchang 330031, P.R.China.

ABSTRACT
Protein function has been observed to rely on select essential sites instead of requiring all sites to be indispensable. Small ubiquitin-related modifier (SUMO) conjugation or sumoylation, which is a highly dynamic reversible process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified, has shown to be especially valuable in cellular biology. Motivated by the significance of SUMO conjugation in biological processes, we report here on the first exploratory assessment whether sumoylation related genetic variability impacts protein functions as well as the occurrence of diseases related to SUMO. Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs. We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system. More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases. It can be anticipated that our method can provide more instructive guidance to identify the mechanisms of genetic diseases.

No MeSH data available.


Related in: MedlinePlus

The data statistics of pathway terms for disease-related sumoylation substrates on the background of normal sumoylation substrates.The blue pillar represent the number of substrates of different pathway terms and the red pillar represent the percentage of the number of substrates of different pathway terms in all substrates. Statistical significance (P-value) gradually increased from top to bottom.
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f4: The data statistics of pathway terms for disease-related sumoylation substrates on the background of normal sumoylation substrates.The blue pillar represent the number of substrates of different pathway terms and the red pillar represent the percentage of the number of substrates of different pathway terms in all substrates. Statistical significance (P-value) gradually increased from top to bottom.

Mentions: In order to further investigate whether the amino acid substitutions that occur in the vicinity of the sumoylation sites impact the state of sumoylation and thus imperceptibly have an influence on the expression of many bodily functions of the human as well as the possible impact of the disease process, we have probed the state of the expression of functional elements with our data such as pathways and gene ontology (GO). Firstly, we used DAVID program5657 to analyze the pathway to further explore functional aspects of disease-related sumoylation substrates. The top 10 statistically significant results (Pā€‰<ā€‰0.05) were listed in Fig. 4. From the results, we could detect that a large portion of disease-related sumoylation substrates were involved in cancer pathways including pathways in cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer. In statistical results obtained, the number of genes involved in the term of "Pathways in cancer" is not simply count up the number of all of other 14 specific cancers such as "pancreatic cancer" and "prostate cancer", etc. But with all of other 14 specific cancers are listed as an individual subtype alone, due to genes known to be functionally altered in each of 14 specific types of cancers are highlighted on their pathway maps only, some of such genes are not highlighted on "Pathways in cancer". The reason is that such oncogenes and tumor suppressor genes are different depending on cancer type58. The occurrence of these cancers is highly related to small ubiquitin-related modifier (SUMO) conjugation or sumoylation. By masking or adding interaction surfaces or by inducing conformational changes, the sumo protein governs protein-protein and protein-DNA interactions and in consequence can lead to changes in protein localization, activity or stability5. There are numerous lines of evidence point to the role for SUMO in carcinogenesis. Many activities of important tumor suppressors and oncoproteins are regulated by sumo including PML, WRN, BLM, c-JUN, c-FOS, TP53 and MDM25960616263 and of several nuclear hormone receptors including estrogen receptor alpha (ERa), progesterone receptor (PR) and AR64, which play a central role in the development of hormone drive breast tumors65, are modified by SUMO in a ligand-dependent manner. For example, mutations of ERa that prevent SUMO modification impair the transcriptional activity of the receptor66. In addition, various components of the SUMO-conjugating machinery are upregulated in several malignancies: UBC9 in melanomas, ovarian cancer and lung adenocarcinomas676869, the SUMO isopeptidase SENP1 in prostate cancer70 and PIAS3 in breast, lung, prostate, colorectal and brain tumors71, indicating that through affecting the state of SUMO, genetic variability might disturb the normal sumoylation of protein and further have an effect on the occurrence of many diseases. The other parts of the result were involved in Cytosolic NDA-sensing signaling pathway, Hypertrophic cardiomyopathy, etc., which also participate in adjusting the process of mechanisms of various functions of human body. Furthermore, dynamic sumoylation hypothetically orchestrates a wide range of cellular processes containing matrix metabolism, inflammation, survival, senescence and autophagy in cell populations. Based on the result of the enrichment of substrates, we also found a number of substrates involved in these processes. We discovered 12 substrates that are involved in "VEGF signaling pathway"(map04370), which may participate in mediating processes of cell survival. There is now much evidence that the binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway could leads to increased endothelial-cell survival72. In addition, there are 28 substrates participate in "MAPK signaling pathway"(map04010) which may adjust processes of inflammation in cell. The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions. Some MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli73. Moreover, Menendez et al. have reported that mTOR could regulate senescence and autophagy during reprogramming of somatic cells to pluripotency74. We also found 8 substrates involved in "mTOR signaling pathway" (map04150) which may have affection on senescence and autophagy in cell populations. The detailed data of pathway enrichment are listed in Table S5. (see Supplementary).


Systematic Analysis of the Genetic Variability That Impacts SUMO Conjugation and Their Involvement in Human Diseases.

Xu HD, Shi SP, Chen X, Qiu JD - Sci Rep (2015)

The data statistics of pathway terms for disease-related sumoylation substrates on the background of normal sumoylation substrates.The blue pillar represent the number of substrates of different pathway terms and the red pillar represent the percentage of the number of substrates of different pathway terms in all substrates. Statistical significance (P-value) gradually increased from top to bottom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495600&req=5

f4: The data statistics of pathway terms for disease-related sumoylation substrates on the background of normal sumoylation substrates.The blue pillar represent the number of substrates of different pathway terms and the red pillar represent the percentage of the number of substrates of different pathway terms in all substrates. Statistical significance (P-value) gradually increased from top to bottom.
Mentions: In order to further investigate whether the amino acid substitutions that occur in the vicinity of the sumoylation sites impact the state of sumoylation and thus imperceptibly have an influence on the expression of many bodily functions of the human as well as the possible impact of the disease process, we have probed the state of the expression of functional elements with our data such as pathways and gene ontology (GO). Firstly, we used DAVID program5657 to analyze the pathway to further explore functional aspects of disease-related sumoylation substrates. The top 10 statistically significant results (Pā€‰<ā€‰0.05) were listed in Fig. 4. From the results, we could detect that a large portion of disease-related sumoylation substrates were involved in cancer pathways including pathways in cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer. In statistical results obtained, the number of genes involved in the term of "Pathways in cancer" is not simply count up the number of all of other 14 specific cancers such as "pancreatic cancer" and "prostate cancer", etc. But with all of other 14 specific cancers are listed as an individual subtype alone, due to genes known to be functionally altered in each of 14 specific types of cancers are highlighted on their pathway maps only, some of such genes are not highlighted on "Pathways in cancer". The reason is that such oncogenes and tumor suppressor genes are different depending on cancer type58. The occurrence of these cancers is highly related to small ubiquitin-related modifier (SUMO) conjugation or sumoylation. By masking or adding interaction surfaces or by inducing conformational changes, the sumo protein governs protein-protein and protein-DNA interactions and in consequence can lead to changes in protein localization, activity or stability5. There are numerous lines of evidence point to the role for SUMO in carcinogenesis. Many activities of important tumor suppressors and oncoproteins are regulated by sumo including PML, WRN, BLM, c-JUN, c-FOS, TP53 and MDM25960616263 and of several nuclear hormone receptors including estrogen receptor alpha (ERa), progesterone receptor (PR) and AR64, which play a central role in the development of hormone drive breast tumors65, are modified by SUMO in a ligand-dependent manner. For example, mutations of ERa that prevent SUMO modification impair the transcriptional activity of the receptor66. In addition, various components of the SUMO-conjugating machinery are upregulated in several malignancies: UBC9 in melanomas, ovarian cancer and lung adenocarcinomas676869, the SUMO isopeptidase SENP1 in prostate cancer70 and PIAS3 in breast, lung, prostate, colorectal and brain tumors71, indicating that through affecting the state of SUMO, genetic variability might disturb the normal sumoylation of protein and further have an effect on the occurrence of many diseases. The other parts of the result were involved in Cytosolic NDA-sensing signaling pathway, Hypertrophic cardiomyopathy, etc., which also participate in adjusting the process of mechanisms of various functions of human body. Furthermore, dynamic sumoylation hypothetically orchestrates a wide range of cellular processes containing matrix metabolism, inflammation, survival, senescence and autophagy in cell populations. Based on the result of the enrichment of substrates, we also found a number of substrates involved in these processes. We discovered 12 substrates that are involved in "VEGF signaling pathway"(map04370), which may participate in mediating processes of cell survival. There is now much evidence that the binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway could leads to increased endothelial-cell survival72. In addition, there are 28 substrates participate in "MAPK signaling pathway"(map04010) which may adjust processes of inflammation in cell. The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions. Some MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli73. Moreover, Menendez et al. have reported that mTOR could regulate senescence and autophagy during reprogramming of somatic cells to pluripotency74. We also found 8 substrates involved in "mTOR signaling pathway" (map04150) which may have affection on senescence and autophagy in cell populations. The detailed data of pathway enrichment are listed in Table S5. (see Supplementary).

Bottom Line: Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs.We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system.More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Nanchang University, Nanchang 330031, P.R.China.

ABSTRACT
Protein function has been observed to rely on select essential sites instead of requiring all sites to be indispensable. Small ubiquitin-related modifier (SUMO) conjugation or sumoylation, which is a highly dynamic reversible process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified, has shown to be especially valuable in cellular biology. Motivated by the significance of SUMO conjugation in biological processes, we report here on the first exploratory assessment whether sumoylation related genetic variability impacts protein functions as well as the occurrence of diseases related to SUMO. Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs. We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system. More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases. It can be anticipated that our method can provide more instructive guidance to identify the mechanisms of genetic diseases.

No MeSH data available.


Related in: MedlinePlus