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

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.

On the identification of potential novel therapeutic targets for spinocerebellar ataxia type 1 (SCA1) neurodegenerative disease using EvoPPI3

“…Further support for the first hypothesis comes from the observation that 5, 25 and 123 predicted H. sapiens interactors are present in the H. sapiens main databases, in the 452 well supported new human Ataxin-1 interactors set (see above), and in the Interactomes/ H. sapiens (PolyQ_22) dataset, respectively ( Figure 4 ). This is in agreement with the conserved functional interactions with the same group of binding partners observed in transgenic flies with the human Ataxin-1 [ 53 – 56 ]. Therefore, using the data from D. melanogaster wt Ataxin-1 mutants, we could validate 123 new human Ataxin-1 interactors.…”

Towards integrated oncogenic marker recognition through mutual information‐based statistically significant feature extraction: an association rule mining based study on cancer expression and methylation profiles

“…Disease-associative KEGG pathways p-value of pathways Supportive literatures UBIAD1 KEGG pathway of (hsa04270) vascular smooth muscle contraction 3.03E-02 [94] NPR2 KEGG pathway of (hsa04270) vascular smooth muscle contraction 3.03E-02 [94] PIAS3 KEGG pathway of (hsa04120) ubiquitin mediated proteolysis 1.80E-02 [96][97][98] GO-BP of protein sumoylation (GO:0016925) 1.52E-02 [99][100][101] GO-MF of small conjugating protein ligase activity (GO:0019787) 1.75E-03 [102] GO-MF of SUMO ligase activity (GO:0019789) 1.54E-02 [100] Table 11. The direct literature evidences of the association between the disease and the participating oncogenes of the top five integrated markers for PC gene expression and methylation datasets.…”

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

“…Somatic lysine mutations targeting the SUMO acceptor sites of substrate proteins may also lead to the dysregulation of SUMOylation and alter protein function in cancer. Interestingly, lysine mutations have been identified in cancer patients with potential functional relevance, but the extent of lysine mutations leading to aberrant SUMOylation is unknown [102,103].…”