Dinkelmann Maria, Spehalski Elizabeth, Stoneham Trina, Buis Jeffrey, Wu Yipin, Sekiguchi JoAnn M, Ferguson David O
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
Nat Struct Mol Biol. 2009 Aug;16(8):808-13. doi: 10.1038/nsmb.1639. Epub 2009 Jul 26.
The Mre11-Rad50-NBS1 (MRN) complex has many roles in response to DNA double-strand breaks, but its functions in repair by nonhomologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in class switch recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end, we have engineered mice that lack the entire MRN complex in B lymphocytes or that possess an intact complex that harbors mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a strong defect in CSR, affecting both the classic and the alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways.
Mre11-Rad50-NBS1（MRN）复合物在应对DNA双链断裂时具有多种作用，但其在非同源末端连接（NHEJ）途径修复中的功能尚不清楚。我们研究了MRN在类别转换重组（CSR）中的需求，CSR是B淋巴细胞中一种需要NHEJ的程序性DNA重排。为此，我们构建了在B淋巴细胞中缺乏整个MRN复合物的小鼠，或者拥有完整复合物但携带缺乏DNA核酸酶活性的突变型Mre11的小鼠。MRN缺陷在CSR中导致强烈缺陷，影响经典和替代NHEJ途径。相比之下，Mre11核酸酶活性的缺失导致较温和的表型，揭示了复合物内的功能分离。我们提出了一个模型，其中MRN稳定远距离断裂并处理DNA末端，以促进经典和替代NHEJ途径的修复。
