BRCA1/BRC-1 and SMC-5/6 regulate DNA repair pathway engagement during C. elegans meiosis
- University of Oregon, United States
- University of Utah, United States
Abstract
The preservation of genome integrity during sperm and egg development is vital for reproductive success. During meiosis, the tumor suppressor BRCA1/BRC-1 and structural maintenance of chromosomes 5/6 (SMC-5/6) complex genetically interact to promote high fidelity DNA double strand break (DSB) repair, but the specific DSB repair outcomes these proteins regulate remain unknown. Using genetic and cytological methods to monitor resolution of DSBs with different repair partners in Caenorhabditis elegans, we demonstrate that both BRC-1 and SMC-5 repress intersister crossover recombination events. Sequencing analysis of conversion tracts from homolog-independent DSB repair events further indicates that BRC-1 regulates intersister/intrachromatid noncrossover conversion tract length. Moreover, we find that BRC-1 specifically inhibits error prone repair of DSBs induced at mid-pachytene. Finally, we reveal functional interactions of BRC-1 and SMC-5/6 in regulating repair pathway engagement: BRC-1 is required for localization of recombinase proteins to DSBs in smc-5 mutants and enhances DSB repair defects in smc-5 mutants by repressing theta-mediated end joining (TMEJ). These results are consistent with a model in which some functions of BRC-1 act upstream of SMC-5/6 to promote recombination and inhibit error-prone DSB repair, while SMC-5/6 acts downstream of BRC-1 to regulate the formation or resolution of recombination intermediates. Taken together, our study illuminates the coordinate interplay of BRC-1 and SMC-5/6 to regulate DSB repair outcomes in the germline.
Data availability
All data generated or analyzed in this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1A, 1C, 1D, 1E, 2A, 2B, 2C, 2D, 3, 4, Figure 1 - figure supplements 2-3, Figure 2 - figure supplements 1-2, and Figure 4 - figure supplements 1-3. Source code files have been provided for Figure 4-figure supplement 3.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R35GM128890)
- Diana E Libuda
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00HD076165)
- Diana E Libuda
National Institute of General Medical Sciences (T32GM007413)
- Erik Toraason
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R25HD070817)
- Alina Salagean
National Institute of General Medical Sciences (T32GM007464)
- David E Almanzar
National Institute of General Medical Sciences (R35GM128804)
- Ofer Rog
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Toraason et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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BRCA1/BRC-1 and SMC-5/6 regulate DNA repair pathway engagement during C. elegans meiosis
eLife 13:e80687.
https://doi.org/10.7554/eLife.80687
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