Recombination is both a means to avoid genome instability and to a process that generates genome instability. In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers; formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis. Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non-crossover outcomes of repair in mitotic cells. We focus on helicases that disassemble recombination intermediates to generate non-crossovers and Holliday junction resolvases that cleave intermediates and can generate crossovers. Our central approach is to take advantage of unique features of Drosophila to address important questions that are difficult to answer with other model systems. In addition, we have developed repair assays to use in human cells, done in vitro biochemical studies, and begun deep sequencing projects. This combination of approaches will help to continue to drive the recombination field forward.

Public Health Relevance

Genetic exchange between homologous chromosomes is essential to ensure that they segregate accurately in meiosis, the specialized cell division that gives rise to eggs and sperm. Errors in recombination can lead to aneuploidy, which is the most common cause of birth defects and miscarriage, however, the same type of exchange in other cells can lead to cancer. This proposal seeks to understand how exchange is promoted in cells undergoing meiosis but avoided in other tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118127-02
Application #
9282741
Study Section
Special Emphasis Panel (ZGM1-TRN-9 (MR))
Program Officer
Deatherage, James F
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$520,113
Indirect Cost
$175,589
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Brady, Morgan M; McMahan, Susan; Sekelsky, Jeff (2018) Loss of Drosophila Mei-41/ATR Alters Meiotic Crossover Patterning. Genetics 208:579-588
Crown, K Nicole; Miller, Danny E; Sekelsky, Jeff et al. (2018) Local Inversion Heterozygosity Alters Recombination throughout the Genome. Curr Biol 28:2984-2990.e3
Bellendir, Stephanie P; Rognstad, Danielle J; Morris, Lydia P et al. (2017) Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates. Nucleic Acids Res 45:5333-5348
Sekelsky, Jeff (2017) DNA Repair in Drosophila: Mutagens, Models, and Missing Genes. Genetics 205:471-490
Hatkevich, Talia; Kohl, Kathryn P; McMahan, Susan et al. (2017) Bloom Syndrome Helicase Promotes Meiotic Crossover Patterning and Homolog Disjunction. Curr Biol 27:96-102
Hartmann, Michaelyn A; Sekelsky, Jeff (2017) The absence of crossovers on chromosome 4 in Drosophila melanogaster: Imperfection or interesting exception? Fly (Austin) 11:253-259
Hatkevich, Talia; Sekelsky, Jeff (2017) Bloom syndrome helicase in meiosis: Pro-crossover functions of an anti-crossover protein. Bioessays 39:
Zapotoczny, Grzegorz; Sekelsky, Jeff (2017) Human Cell Assays for Synthesis-Dependent Strand Annealing and Crossing over During Double-Strand Break Repair. G3 (Bethesda) 7:1191-1199
Holsclaw, Julie Korda; Sekelsky, Jeff (2017) Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1. Genetics 206:467-480
Romero, Noelle-Erin; Matson, Steven W; Sekelsky, Jeff (2016) Biochemical Activities and Genetic Functions of the Drosophila melanogaster Fancm Helicase in DNA Repair. Genetics 204:531-541