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Michael Matunis, Ph.D.

Additional Information

Research Program

The Roles of Ubiquitin-like Modifiers in Regulating the Localization and Function of DNA Repair Proteins

Genomic instability is a major factor that contributes to the development of human cancers.  Cells therefore possess a variety of mechanisms to detect and repair DNA lesions that could result in permanent and deleterious genetic changes.  The small ubiquitin related modifier (SUMO) plays a prominent role in regulating cellular processes linked to the maintenance of genome integrity, with cells deficient in components of the SUMO pathway displaying defects in DNA replication, DNA repair and chromosome segregation.  In the past several years, numerous DNA replication and repair factors have been identified as substrates for SUMO modification, however, the exact molecular mechanisms by which SUMO modification exerts its effects on these proteins still remain poorly understood.

We have recently demonstrated that SUMO-2 modification regulates the trafficking of one DNA repair protein, the Bloom’s syndrome DNA helicase (BLM), between PML nuclear bodies and DNA damage induced foci.  Based on our preliminary studies, we hypothesize that SUMO-2 modification functions as a general mechanism for controlling DNA replication and repair proteins by regulating their dynamic distribution between PML nuclear bodies and sites of DNA damage.  Our Driving Biological Project focuses on testing this hypothesis through:

  • Investigation of the roles that SUMO-2 modification and SUMO-2 binding play in targeting DNA repair proteins to PML nuclear bodies. 

  • Investigation of the role of that phosphorylation plays in regulating the SUMO-2 modification and SUMO-2 binding activities of BLM.

  • Identification of protein-protein interactions mediated by SUMO-2 modification of BLM

Fig SUMOylation Model

This figure illustrates a possible mechanism for SUMOylation mediated by noncovalent SUMO binding.  A SUMO-interaction motif (SIM)-containing protein binds to SUMO that is covalently linked to the active site cysteine of Ubc9.  Binding enhances the local concentration of Ubc9 in the vicinity of the substrate, allowing Ubc9 to recognize lysine residues not contained within optimal consensus SUMOylation motifs.  SUMO is subsequently covalently conjugated to the substrate and Ubc9 is released.  Paralog-selective SUMOylation is determined by the relative affinities of the SIM for SUMO-1 or SUMO-2.

 
 
 
 
 
 

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