SUMO-1 is a 101 amino acid polypeptide that shares 18 percent sequence identity with ubiquitin. Like ubiquitin, SUMO-1 is posttransationally conjugated to a significant number of intracellular proteins. However, SUMO-1 conjugation appears to regulate the function and/or localization of targeted substrates, rather than their proteolysis. SUMO-1 conjugation has been implicated, either directly or indirectly, as a regulator of a wide range of important cell functions. Proteins identified as substrates for SUMO-1 conjugation include RanGAP1 (a regulator of nucleocytoplasmic transport), PML and Sp100 (components of intranuclear structures linked to cancer and neurodegenerative disease), and IkappaBalpha (a regulator of signaling pathways that control immune and inflammatory responses). SUMO-1 conjugation has also been implicated as a regulator of the cell cycle and DNA repair. In spite of the preliminary indications that SUMO-1 conjugation regulates a host of cell functions, the precise effects that SUMO-1 conjugation has on individual proteins, and consequently on cellular processes, remains unclear.
The Specific Aims outlined in this proposal are designed to provide a more detailed understanding of SUMO- 1 conjugation, its specific effects on protein function, and its more global effects on cellular processes. These goals will be achieved through analysis of the factors and signals regulating SUMO-1 conjugation and deconjugation, characterization of novel SUMO-1 substrates, and characterization of the SUMO-1 related protein, SUMO-2. The hypothesis that SUMO-1 conjugation is regulated by E3-like protein ligases, as well as by deconjugating enzymes, will be investigated. Also, the functional relationships between SUMO-1 conjugation and PML nuclear bodies will be investigated through analysis of BLM, a novel SUMO-1/SUMO-2 substrate, and through analysis of substrates associated with the XY body of pachytene spermatocytes. The hypothesis that the XY body and PML nuclear bodies are functionally related and share common SUMO-1 conjugates will also be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060980-05
Application #
6708091
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Shapiro, Bert I
Project Start
2000-03-01
Project End
2005-11-30
Budget Start
2004-03-01
Budget End
2005-11-30
Support Year
5
Fiscal Year
2004
Total Cost
$251,790
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Lee, Christine C; Li, Bing; Yu, Hongtao et al. (2018) Sumoylation promotes optimal APC/C Activation and Timely Anaphase. Elife 7:
Lee, Christine C; Li, Bing; Yu, Hongtao et al. (2018) A Method for SUMO Modification of Proteins in vitro. Bio Protoc 8:
Uzoma, Ijeoma; Hu, Jianfei; Cox, Eric et al. (2018) Global Identification of Small Ubiquitin-related Modifier (SUMO) Substrates Reveals Crosstalk between SUMOylation and Phosphorylation Promotes Cell Migration. Mol Cell Proteomics 17:871-888
Cox, Eric; Hwang, Woochang; Uzoma, Ijeoma et al. (2017) Global Analysis of SUMO-Binding Proteins Identifies SUMOylation as a Key Regulator of the INO80 Chromatin Remodeling Complex. Mol Cell Proteomics 16:812-823
Newman, Heather A; Meluh, Pamela B; Lu, Jian et al. (2017) A high throughput mutagenic analysis of yeast sumo structure and function. PLoS Genet 13:e1006612
Lombardi, Patrick M; Matunis, Michael J; Wolberger, Cynthia (2017) RAP80, ubiquitin and SUMO in the DNA damage response. J Mol Med (Berl) 95:799-807
Reiter, Katherine H; Ramachandran, Anita; Xia, Xue et al. (2016) Characterization and Structural Insights into Selective E1-E2 Interactions in the Human and Plasmodium falciparum SUMO Conjugation Systems. J Biol Chem 291:3860-70
Lee, Christine C; Matunis, Michael J (2016) Resolving Chromatin Bridges With SIMs, SUMOs and PICH. Cell Cycle 15:2547-2548
McLaughlin, Dylan; Coey, Christopher T; Yang, Wei-Chih et al. (2016) Characterizing Requirements for Small Ubiquitin-like Modifier (SUMO) Modification and Binding on Base Excision Repair Activity of Thymine-DNA Glycosylase in Vivo. J Biol Chem 291:9014-24

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