Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation

Jessica P. Lao, Veronica Cloud, Chu Chun Huang, Jennifer Grubb, Drew Thacker, Chih Ying Lee, Michael E. Dresser, Neil Hunter, Douglas K. Bishop

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

During meiosis, repair of programmed DNA double-strand breaks (DSBs) by recombination promotes pairing of homologous chromosomes and their connection by crossovers. Two DNA strand-exchange proteins, Rad51 and Dmc1, are required for meiotic recombination in many organisms. Studies in budding yeast imply that Rad51 acts to regulate Dmc1's strand exchange activity, while its own exchange activity is inhibited. However, in a dmc1 mutant, elimination of inhibitory factor, Hed1, activates Rad51's strand exchange activity and results in high levels of recombination without participation of Dmc1. Here we show that Rad51-mediated meiotic recombination is not subject to regulatory processes associated with high-fidelity chromosome segregation. These include homolog bias, a process that directs strand exchange between homologs rather than sister chromatids. Furthermore, activation of Rad51 does not effectively substitute for Dmc1's chromosome pairing activity, nor does it ensure formation of the obligate crossovers required for accurate homolog segregation. We further show that Dmc1's dominance in promoting strand exchange between homologs involves repression of Rad51's strand-exchange activity. This function of Dmc1 is independent of Hed1, but requires the meiotic kinase, Mek1. Hed1 makes a relatively minor contribution to homolog bias, but nonetheless this is important for normal morphogenesis of synaptonemal complexes and efficient crossing-over especially when DSB numbers are decreased. Super-resolution microscopy shows that Dmc1 also acts to organize discrete complexes of a Mek1 partner protein, Red1, into clusters along lateral elements of synaptonemal complexes; this activity may also contribute to homolog bias. Finally, we show that when interhomolog bias is defective, recombination is buffered by two feedback processes, one that increases the fraction of events that yields crossovers, and a second that we propose involves additional DSB formation in response to defective homolog interactions. Thus, robust crossover homeostasis is conferred by integrated regulation at initiation, strand-exchange and maturation steps of meiotic recombination.

Original languageEnglish (US)
Article numbere1003978
JournalPLoS Genetics
Volume9
Issue number12
DOIs
StatePublished - 2013

Fingerprint

Genetic Recombination
recombination
synaptonemal complex
Synaptonemal Complex
Chromosome Pairing
chromosome
chromosome pairing
chromosome segregation
chromatids
crossing over
DNA
meiosis
dominance (genetics)
morphogenesis
microscopy
homeostasis
Chromosome Segregation
phosphotransferases (kinases)
Saccharomycetales
Chromatids

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Lao, J. P., Cloud, V., Huang, C. C., Grubb, J., Thacker, D., Lee, C. Y., ... Bishop, D. K. (2013). Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation. PLoS Genetics, 9(12), [e1003978]. https://doi.org/10.1371/journal.pgen.1003978

Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation. / Lao, Jessica P.; Cloud, Veronica; Huang, Chu Chun; Grubb, Jennifer; Thacker, Drew; Lee, Chih Ying; Dresser, Michael E.; Hunter, Neil; Bishop, Douglas K.

In: PLoS Genetics, Vol. 9, No. 12, e1003978, 2013.

Research output: Contribution to journalArticle

Lao, JP, Cloud, V, Huang, CC, Grubb, J, Thacker, D, Lee, CY, Dresser, ME, Hunter, N & Bishop, DK 2013, 'Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation', PLoS Genetics, vol. 9, no. 12, e1003978. https://doi.org/10.1371/journal.pgen.1003978
Lao, Jessica P. ; Cloud, Veronica ; Huang, Chu Chun ; Grubb, Jennifer ; Thacker, Drew ; Lee, Chih Ying ; Dresser, Michael E. ; Hunter, Neil ; Bishop, Douglas K. / Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation. In: PLoS Genetics. 2013 ; Vol. 9, No. 12.
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