RESUMO
Meiotic recombination initiates following the formation of DNA double-strand breaks (DSBs) by the Spo11 endonuclease early in prophase I, at discrete regions in the genome coined "hot spots." In mammals, meiotic DSB site selection is directed in part by sequence-specific binding of PRDM9, a polymorphic histone H3 (H3K4Me3) methyltransferase. However, other chromatin features needed for meiotic hot spot specification are largely unknown. Here we show that the recombinogenic cores of active hot spots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these open chromatin-associated histone marks is dynamic and is manifest at spermatogonia and/or pre-leptotene-stage cells, which facilitates PRDM9 binding and access for Spo11 to direct the formation of DSBs, which are initiated at the leptotene stage. Importantly, manipulating histone acetylase and deacetylase activities established that histone acetylation marks are necessary for both hot spot activity and crossover resolution. We conclude that there are functional roles for histone acetylation marks at mammalian meiotic recombination hot spots.
Assuntos
Código das Histonas , Recombinação Homóloga , Meiose , Animais , Endodesoxirribonucleases/metabolismo , Regulação da Expressão Gênica , Histonas/metabolismo , Recombinação Homóloga/genética , Meiose/genética , Metilação , Camundongos Endogâmicos C57BL , Modelos Biológicos , Prófase/genéticaRESUMO
The stereodivergent behavior of allenyl(cyano)- and allenyl(alkyl)cuprates toward aldehydes, providing a selective preparation of both syn- and anti-homopropargylic alcohols, is described. This study, which combines both experimental and theoretical support, shows that the copper nontransferred "dummy ligand" controls the localization of the lithium cation with respect to the allenylcuprate moiety. As a consequence, Li(+) acts as a Lewis acid activator but also controls the diastereoselectivity during the addition of allenylcuprates onto aldehydes. The combined high selectivity, efficiency, and versatility of these cuprate compounds opens the way to new one-pot synthetic procedures, as illustrated by the combined Klein rearrangement/transmetalation methodology described herein.
