Microhomology-mediated end joining (MMEJ) repairs DNA breaks by annealing 2-20 bp of flanking microhomology (MH), yielding repair products with deletions of MH and inter-MH sequences. MMEJ is thus a highly error prone repair mechanism with a strong propensity to lead to chromosomal translocations and cancer-causing mutations. Accordingly, the breakpoint junctions of many oncogenic chromosomal translocations feature MH, underscoring the importance of this mechanism for the development chromosome instability and carcinogenesis. Emerging evidence also suggests that MMEJ is an evolutionarily conserved mechanism from yeast to human, and it is involved in the repair of DNA double strand breaks, telomere fusion and immune receptor development. However, we do not know when and where MMEJ operates or how it coordinates and competes against other DNA repair processes. We also do not know if the chromatin and nuclear landscape surrounding DNA breaks impinge on the outcomes of MMEJ and chromosomal aberration formation. It is thus imperative to define the basic mechanism of MMEJ and its genetic and biochemical attributes in a model system with the most tractability. Recently, we have developed both chromosome-based and plasmid-based systems that produce MMEJ repair in budding yeast cells at a high frequency. These systems are most amenable for defining the spatial and temporal patterns of MMEJ and its relationship to canonical repair pathways. Employing these assays, we will test if MMEJ occurs at specific times in the cell cycle and is restricted to a unique nuclear compartment. We will also initiate a powerful genetic screen for new MMEJ genes by combining our plasmid-based MMEJ assay with the bar-coded array or a next generation sequencing technique with the nonessential gene deletion library. Using an approach combining genetics, cell biology and genomic techniques, we also plan to address how MMEJ bypasses end tethering and chromosome territories, two barriers against the formation of chromosomal translocation. Together, the outcomes of this proposal will shed light on the fundamental principles of MMEJ and its contribution to chromosomal instability in many human diseases including cancer.

Public Health Relevance

Presence of microhomology is the frequent feature of pathogenic chromosomal translocation breakpoints in humans and has been implicated in the error prone repair of DNA breaks in both yeast and vertebrate cells. However, we do not know how microhomology directs DNA repair and chromosome aberrations. The proposed research will address these fundamental biological questions pertaining to wide ranges of human genetic diseases and cancers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Willis, Kristine Amalee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center
Other Basic Sciences
Schools of Medicine
San Antonio
United States
Zip Code
Wang, Weibin; Daley, James M; Kwon, Youngho et al. (2018) A DNA nick at Ku-blocked double-strand break ends serves as an entry site for exonuclease 1 (Exo1) or Sgs1-Dna2 in long-range DNA end resection. J Biol Chem 293:17061-17069
Eichmiller, Robin; Medina-Rivera, Melisa; DeSanto, Rachel et al. (2018) Coordination of Rad1-Rad10 interactions with Msh2-Msh3, Saw1 and RPA is essential for functional 3' non-homologous tail removal. Nucleic Acids Res 46:5075-5096
Obeidat, Mohammad; McConnell, Kristen A; Li, Xiaolei et al. (2018) DNA double-strand breaks as a method of radiation measurements for therapeutic beams. Med Phys 45:3460-3465
Seol, Ja-Hwan; Holland, Cory; Li, Xiaolei et al. (2018) Distinct roles of XPF-ERCC1 and Rad1-Rad10-Saw1 in replication-coupled and uncoupled inter-strand crosslink repair. Nat Commun 9:2025
Sinha, Supriya; Villarreal, Diana; Shim, Eun Yong et al. (2016) Risky business: Microhomology-mediated end joining. Mutat Res 788:17-24
Liu, Yaqi; Sung, Sihyun; Kim, Youngran et al. (2016) ATP-dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex. EMBO J 35:743-58
Che, Jun; Smith, Stephanie; Kim, Yoo Jung et al. (2015) Hyper-Acetylation of Histone H3K56 Limits Break-Induced Replication by Inhibiting Extensive Repair Synthesis. PLoS Genet 11:e1004990
Sung, Sihyun; Li, Fuyang; Park, Young Bong et al. (2014) DNA end recognition by the Mre11 nuclease dimer: insights into resection and repair of damaged DNA. EMBO J 33:2422-35
Sarangi, Prabha; Altmannova, Veronika; Holland, Cory et al. (2014) A versatile scaffold contributes to damage survival via sumoylation and nuclease interactions. Cell Rep 9:143-152
Sarangi, Prabha; Bartosova, Zdenka; Altmannova, Veronika et al. (2014) Sumoylation of the Rad1 nuclease promotes DNA repair and regulates its DNA association. Nucleic Acids Res 42:6393-404

Showing the most recent 10 out of 23 publications