Homologous recombination (HR) is an essential mechanism that maintains genomic integrity in cells by repairing double-strand breaks and repairing damaged replication forks. The RAD51 recombinase catalyzes the central step in the HR pathway, forming joint molecules through homology-dependent strand invasion. The BLM helicase, which is the gene mutated in Bloom's syndrome (BS), regulates RAD51. BLM can promote RAD51 function, for example by generating substrate for RAD51 binding, or it can inhibit RAD51 function by unwinding the products of RAD51 catalysis, which prevents the accumulation of toxic recombination intermediates. Thus, through its regulation of RAD51, BLM has both pro- and anti-recombinogenic functions in HR. We have shown that BLM is modified by small ubiquitin-related modifiers (SUMOs) and that BLM SUMOylation regulates BLM's functions at stalled replication forks, stimulating HR repair. In addition, RAD51 is SUMO-binding, and BLM SUMOylation stimulates BLM's interaction with RAD51 in vitro. Our findings support a model in which BLM SUMOylation controls a switch between BLM's anti- recombinogenic and pro-recombinogenic functions. To test this hypothesis, we have four specific aims: (1) characterization of the role of BLM SUMOylation in stabilization of replication forks;(2) characterization of the role of RAD51 SUMO binding in replication fork stability and HR repair;(3) analysis of the effects of BLM SUMOylation on BLM's biochemical activities and RAD51 function;and (4) analysis of the effects of BLM SUMOylation and RAD51 SUMO binding in genomic integrity. Our studies will elucidate the molecular mechanisms that regulate HR at damaged replication forks, providing insights into the dynamic functions of BLM and RAD51 in HR repair and leading to a deeper understanding of how these functions are regulated by the SUMO pathway. Because HR repair mechanisms are often dysregulated in cancer cells, our work will lead to a better understanding of genomic instability in cancer and will facilitate the exploitation of this instability in cancer treatments.

Public Health Relevance

The homologous recombination pathway repairs DNA damage that arises during the synthesis of DNA. Unregulated homologous recombination causes problems during repair of DNA synthesis failures, and it generates chromosome instability. Chromosome instability is a common feature of cancer cells, and it speeds the development of cancer. The purpose of our research is to characterize the molecular mechanisms that regulate homologous recombination in human cells, which will help in the identification of therapeutic targets for cancer treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Cunniff, Christopher; Djavid, Amir Reza; Carrubba, Steven et al. (2018) Health supervision for people with Bloom syndrome. Am J Med Genet A 176:1872-1881
de Renty, Christelle; Ellis, Nathan A (2017) Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. Ageing Res Rev 33:36-51
Cunniff, Christopher; Bassetti, Jennifer A; Ellis, Nathan A (2017) Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Mol Syndromol 8:4-23
Hulur, Imge; Gamazon, Eric R; Skol, Andrew D et al. (2015) Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC Genomics 16:138
Xicola, Rosa M; Gagnon, Molly; Clark, Julia R et al. (2014) Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. Clin Cancer Res 20:4962-70
Kupfer, Sonia S; Skol, Andrew D; Hong, Ellie et al. (2014) Shared and independent colorectal cancer risk alleles in TGF?-related genes in African and European Americans. Carcinogenesis 35:2025-30
Pibiri, Fabio; Kittles, Rick A; Sandler, Robert S et al. (2014) Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control 25:561-70
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
Ellis, Nathan A; Offit, Kenneth (2012) Heterozygous mutations in DNA repair genes and hereditary breast cancer: a question of power. PLoS Genet 8:e1003008