SUMOs (small ubiquitin-related modifiers) are ~100 amino acid proteins that are posttranslationally and covalently conjugated to hundreds of other proteins and thereby regulate a wide range of cellular processes. We have found that sumoylation, like ubiquitination and phosphorylation, is an essential regulator of mitosis in mammalian cells. Mammals express three SUMO paralogs: SUMO-1, SUMO-2 and SUMO-3 (because SUMO-2 and SUMO-3 are 96% identical, they are referred to as SUMO-2/3). Our findings indicate that SUMO-1 and SUMO-2/3 are conjugated to unique subsets of proteins during mitosis and that they regulate distinct processes. However, many unanswered questions still exist. Many of the relevant targets of SUMO-1 and SUMO-2/3 modification remain to be identified and characterized, and mechanisms regulating their temporal modification in mitosis are not known. In addition, the specific molecular effects of SUMO-1 and SUMO-2/3 modification on their targets, and how these effects facilitate progression through mitosis, are still poorly understood. The goals of the research proposed in this renewal grant application are to address these questions and develop a detailed molecular understanding of how sumoylation affects progression through mitosis. These goals will be achieved through four specific aims: (1) We will define the roles that SUMO-2/3 modification and binding play in the targeting and assembly of kinetochore-associated proteins during mitosis. (2) We will identify and characterize molecular mechanisms regulating the temporal and spatial sumoylation of proteins during mitosis. (3) We will identify and characterize chromosome-associated proteins sumoylated during anaphase and telophase. (4) We will investigate the biophysical properties and functions of polymeric SUMO-2/3 chains and mitosis-related chain-binding proteins.
Understanding the factors and signals that regulate normal cell division is essential for a full understanding of the causes of human cancer and for development of new anti-cancer therapies. We have identified sumoylation (the covalent linkage of the SUMO protein to other cellular proteins) as a critical process required for normal cell division. Our studies are designed to provide a more complete understanding of how sumoylation regulates cell division at the molecular level. Knowledge gained from these studies has the potential to lead to the development of new strategies for both the detection and for the treatment of human cancers.
|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|
|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|
|Cox, Eric; Uzoma, Ijeoma; Guzzo, Catherine et al. (2015) Identification of SUMO E3 ligase-specific substrates using the HuProt human proteome microarray. Methods Mol Biol 1295:455-63|
|Zhang, Ke; Donnelly, Christopher J; Haeusler, Aaron R et al. (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56-61|
|CubeÃ±as-Potts, Caelin; Srikumar, Tharan; Lee, Christine et al. (2015) Identification of SUMO-2/3-modified proteins associated with mitotic chromosomes. Proteomics 15:763-72|
|Coey, Christopher T; Fitzgerald, Megan E; Maiti, Atanu et al. (2014) E2-mediated small ubiquitin-like modifier (SUMO) modification of thymine DNA glycosylase is efficient but not selective for the enzyme-product complex. J Biol Chem 289:15810-9|
|CubeÃ±as-Potts, Caelin; Goeres, Jacqueline D; Matunis, Michael J (2013) SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis. Mol Biol Cell 24:3483-95|
|Ouyang, Karen J; Yagle, Mary K; Matunis, Michael J et al. (2013) BLM SUMOylation regulates ssDNA accumulation at stalled replication forks. Front Genet 4:167|
|CubeÃ±as-Potts, Caelin; Matunis, Michael J (2013) SUMO: a multifaceted modifier of chromatin structure and function. Dev Cell 24:1-12|
|Reiter, Katherine; Mukhopadhyay, Debaditya; Zhang, Hong et al. (2013) Identification of biochemically distinct properties of the small ubiquitin-related modifier (SUMO) conjugation pathway in Plasmodium falciparum. J Biol Chem 288:27724-36|
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