人源错配修复蛋白4-人源错配修复蛋白5识别霍利迪连接体，并形成一种拥抱同源染色体的减数分裂特异性滑动夹。

hMSH4-hMSH5 recognizes Holliday Junctions and forms a meiosis-specific sliding clamp that embraces homologous chromosomes.

作者信息

Snowden Timothy, Acharya Samir, Butz Charles, Berardini Mark, Fishel Richard

机构信息

Genetics and Molecular Biology Program, Kimmel Cancer Center, BLSB 933, 233 South 10th Street, Philadelphia, PA 19107, USA.

出版信息

Mol Cell. 2004 Aug 13;15(3):437-51. doi: 10.1016/j.molcel.2004.06.040.

DOI:10.1016/j.molcel.2004.06.040

PMID:15304223

Abstract

Five MutS homologs (MSH), which form three heterodimeric protein complexes, have been identified in eukaryotes. While the human hMSH2-hMSH3 and hMSH2-hMSH6 heterodimers operate primarily in mitotic mismatch repair (MMR), the biochemical function(s) of the meiosis-specific hMSH4-hMSH5 heterodimer is unknown. Here, we demonstrate that purified hMSH4-hMSH5 binds uniquely to Holliday Junctions. Holliday Junctions stimulate the hMSH4-hMSH5 ATP hydrolysis (ATPase) activity, which is controlled by Holliday Junction-provoked ADP-->ATP exchange. ATP binding by hMSH4-hMSH5 induces the formation of a hydrolysis-independent sliding clamp that dissociates from the Holliday Junction crossover region, embracing two homologous duplex DNA arms. Fundamental differences between hMSH2-hMSH6 and hMSH4-hMSH5 Holliday Junction recognition are detailed. Our results support the attractive possibility that hMSH4-hMSH5 stabilizes and preserves a meiotic bimolecular double-strand break repair (DSBR) intermediate.

摘要

在真核生物中已鉴定出五种MutS同源物（MSH），它们形成三种异二聚体蛋白复合物。人类的hMSH2 - hMSH3和hMSH2 - hMSH6异二聚体主要在有丝分裂错配修复（MMR）中起作用，而减数分裂特异性的hMSH4 - hMSH5异二聚体的生化功能尚不清楚。在此，我们证明纯化的hMSH4 - hMSH5特异性结合霍利迪连接体。霍利迪连接体刺激hMSH4 - hMSH5的ATP水解（ATP酶）活性，该活性由霍利迪连接体引发的ADP→ATP交换控制。hMSH4 - hMSH5与ATP结合会诱导形成一种不依赖水解的滑动夹，该滑动夹从霍利迪连接体交叉区域解离，环绕两条同源双链DNA臂。详细阐述了hMSH2 - hMSH6与hMSH4 - hMSH5对霍利迪连接体识别的根本差异。我们的结果支持了一种有吸引力的可能性，即hMSH4 - hMSH5稳定并保留减数分裂双分子双链断裂修复（DSBR）中间体。