Center for Gene Regulation in Health and Disease and Department of Biological Sciences, Cleveland State University, Cleveland, OH 44115, USA.
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Dev Cell. 2020 May 18;53(4):458-472.e5. doi: 10.1016/j.devcel.2020.04.010. Epub 2020 May 7.
Meiotic pairing between parental chromosomes (homologs) is required for formation of haploid gametes. Homolog pairing depends on recombination initiation via programmed double-strand breaks (DSBs). Although DSBs appear prior to pairing, the homolog, rather than the sister chromatid, is used as repair partner for crossing over. Here, we show that Mph1, the budding yeast ortholog of Fanconi anemia helicase FANCM, prevents precocious DSB strand exchange between sister chromatids before homologs have completed pairing. By dissociating precocious DNA displacement loops (D-loops) between sister chromatids, Mph1 ensures high levels of crossovers and non-crossovers between homologs. Later-occurring recombination events are protected from Mph1-mediated dissociation by synapsis protein Zip1. Increased intersister repair in absence of Mph1 triggers a shift among remaining interhomolog events from non-crossovers to crossover-specific strand exchange, explaining Mph1's apparent anti-crossover function. Our findings identify temporal coordination between DSB strand exchange and homolog pairing as a critical determinant for recombination outcome.
在形成单倍体配子的过程中，双亲染色体（同源染色体）之间需要减数分裂配对。同源染色体配对依赖于通过程序性双链断裂（DSBs）启动的重组。尽管 DSBs 出现在配对之前，但同源染色体而非姐妹染色单体被用作交叉的修复伙伴。在这里，我们表明，芽殖酵母范可尼贫血解旋酶 FANCM 的同源物 Mph1 可防止同源染色体完成配对之前姐妹染色单体之间过早的 DSB 链交换。通过解离姐妹染色单体之间过早的 DNA 置换环（D-loops），Mph1 确保了同源染色体之间高频率的交叉和非交叉。随后发生的重组事件通过联会蛋白 Zip1 免受 Mph1 介导的解离的保护。在没有 Mph1 的情况下增加姐妹间修复会触发剩余的同源事件从非交叉到交叉特异性链交换的转变，这解释了 Mph1 明显的抗交叉功能。我们的发现确定了 DSB 链交换和同源染色体配对之间的时间协调作为重组结果的关键决定因素。
