MutSα and MutSβ play important roles in DNA mismatch repair and are linked to inheritable cancers and degenerative disorders. Here, we show that MSH2 and MSH3, the two components of MutSβ, bind SLX4 protein, a scaffold for the assembly of the SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) trinuclease complex. SMX promotes the resolution of Holliday junctions (HJs), which are intermediates in homologous recombinational repair. We find that MutSβ binds HJs and stimulates their resolution by SLX1-SLX4 or SMX in reactions dependent upon direct interactions between MutSβ and SLX4. In contrast, MutSα does not stimulate HJ resolution. MSH3-depleted cells exhibit reduced sister chromatid exchanges and elevated levels of homologous recombination ultrafine bridges (HR-UFBs) at mitosis, consistent with defects in the processing of recombination intermediates. These results demonstrate a role for MutSβ in addition to its established role in the pathogenic expansion of CAG/CTG trinucleotide repeats, which is causative of myotonic dystrophy and Huntington's disease.

中文翻译：

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MutSβ 通过 SMX 复合体刺激霍利迪结分辨率。

MutSα 和 MutSβ 在 DNA 错配修复中发挥重要作用，并与可遗传的癌症和退行性疾病有关。在这里，我们展示了 MutSβ 的两个成分 MSH2 和 MSH3 结合 SLX4 蛋白，SLX4 蛋白是组装 SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) 三核酸酶复合物的支架。SMX 促进了霍利迪连接 (HJ) 的分辨率，后者是同源重组修复的中间体。我们发现 MutSβ 结合 HJs 并通过 SLX1-SLX4 或 SMX 在依赖于 MutSβ 和 SLX4 之间直接相互作用的反应中刺激它们的分解。相比之下，MutSα 不会刺激 HJ 分辨率。MSH3 耗尽的细胞在有丝分裂时表现出姐妹染色单体交换减少和同源重组超细桥 (HR-UFB) 水平升高，这与重组中间体的加工缺陷一致。