Nature2014-06-16 3:51 PM

DNA“双链断裂”的控制 Homologue engagement controls meiotic DNA break number and distribution

论文摘要 

基因添加技術已被用來治療一些遺傳病,但毒性仍是一大問題。這使得基因修復(僅以缺陷基因為目標)成為一個有吸引力的替代方案。Luigi Naldini及同事在本文中報告了在人類造血幹細胞(HSCs)中成功進行的定向基因組編輯。他們通過量身定制輸送平台和培養條件克服了以前所存在的障礙。這種方法的治療潛力通過向來自健康供者和一位“與X-相關的嚴重複合免疫缺陷症”(SCID-X1)患者的HSCs的IL2RG基因的一個突變熱點中插入一個糾正性cDNA得到了演示。通過基因編輯的HSCs產生功能性淋巴樣細胞,後者相對於那些攜帶破壞性IL2RG突變的淋巴樣細胞具有一個選擇性生長優勢。

Abstract 

Meiotic recombination promotes genetic diversification as well as pairing and segregation of homologous chromosomes, but the double-strand breaks (DSBs) that initiate recombination are dangerous lesions that can cause mutation or meiotic failure. How cells control DSBs to balance between beneficial and deleterious outcomes is not well understood. Here we test the hypothesis that DSB control involves a network of intersecting negative regulatory circuits. Using multiple complementary methods, we show that DSBs form in greater numbers in Saccharomyces cerevisiae cells lacking ZMM proteins, a suite of recombination-promoting factors traditionally regarded as acting strictly downstream of DSB formation. ZMM-dependent DSB control is genetically distinct from a pathway tying break formation to meiotic progression through the Ndt80 transcription factor. These counterintuitive findings suggest that homologous chromosomes that have successfully engaged one another stop making breaks. Genome-wide DSB maps uncover distinct responses by different subchromosomal domains to the ZMM mutation zip3 (also known as cst9), and show that Zip3 is required for the previously unexplained tendency of DSB density to vary with chromosome size. Thus, feedback tied to ZMM function contributes in unexpected ways to spatial patterning of recombination.

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