The human genome contains many at-risk sequences that are prone to mutations including diverse repeated sequences, segmental duplications and regions of copy number variations. Such repetitive sequence elements can cause genome rearrangements through non-allelic homologous recombination (HR). Many human diseases are known to be caused by chromosomal rearrangements mediated by non-allelic HR. Moreover, many cancers exhibit ongoing genome rearrangements, stimulated by numerous at-risk sequences in the genome. The yeast Saccharomyces cerevisiae provides a powerful model system to study genome rearrangements. Despite that many pathways have been found to suppress genome rearrangements, the understanding of how duplication-mediated genome rearrangements are specifically suppressed remains rudimentary. Sumoylation is an evolutionarily conserved post-translational modification of proteins and it is known to regulate many nuclear activities includin gene transcription, chromosome segregation, DNA replication and repair. We have discovered a new function of protein sumoylation in suppression of duplication- mediated genome rearrangement and found that the SUMO pathway is by far the most important pathway in preventing this type of genome rearrangements. In the proposed studies, we will characterize the genetics and biochemistry of the SUMO pathway focusing on its function in genome maintenance. We will pursue the following specific aims: First, we will characterize the role of essential genes in genome maintenance. Second, we will determine the enzyme-substrate relationship in the SUMO pathway, focusing on the function and substrates of SUMO-specific isopeptidase. Third, we will study how sumoylation of Mms21-specific substrates contribute to genome maintenance. In all of our studies, we will employ a combination of genetic, biochemical and proteomic approaches to study how the SUMO pathway specifically prevents duplication-mediated genome rearrangements, which are expected to provide new insights into the genetic basis of human cancers.

Public Health Relevance

Chromosomal rearrangements are a hallmark of cells derived from many human diseases especially cancers. Protein sumoylation is an evolutionarily conserved post-translational modification in eukaryotic cells. We have found that protein sumoylation has a major role in the suppression of duplication- mediated genome rearrangements. The proposed project will characterize the genetics and biochemistry of the SUMO pathway and how it maintains genome integrity. Insights from our studies will help to understand the genetics of human cancers, lead to the development of new tools for cancer diagnostics as well as improved chemotherapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM116897-04
Application #
9545820
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Barski, Oleg
Project Start
2015-09-30
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Ludwig Institute for Cancer Research Ltd
Department
Type
DUNS #
627922248
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Liang, Jason; Li, Bin-Zhong; Tan, Alexander P et al. (2018) SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements. PLoS Genet 14:e1007250
de Albuquerque, Claudio Ponte; Suhandynata, Raymond T; Carlson, Christopher R et al. (2018) Binding to small ubiquitin-like modifier and the nucleolar protein Csm1 regulates substrate specificity of the Ulp2 protease. J Biol Chem 293:12105-12119
Local, Andrea; Huang, Hui; Albuquerque, Claudio P et al. (2018) Identification of H3K4me1-associated proteins at mammalian enhancers. Nat Genet 50:73-82
Gu, Yuchao; Albuquerque, Claudio P; Braas, Daniel et al. (2017) mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. Mol Cell 67:128-138.e7
Liang, Jason; Singh, Namit; Carlson, Christopher R et al. (2017) Recruitment of a SUMO isopeptidase to rDNA stabilizes silencing complexes by opposing SUMO targeted ubiquitin ligase activity. Genes Dev 31:802-815
de Albuquerque, Claudio Ponte; Liang, Jason; Gaut, Nathaniel James et al. (2016) Molecular Circuitry of the SUMO (Small Ubiquitin-like Modifier) Pathway in Controlling Sumoylation Homeostasis and Suppressing Genome Rearrangements. J Biol Chem 291:8825-35
Albuquerque, Claudio P; Yeung, Eyan; Ma, Shawn et al. (2015) A Chemical and Enzymatic Approach to Study Site-Specific Sumoylation. PLoS One 10:e0143810