Abstract

SLX4 provides a molecular scaffold for the assembly of multiple protein complexes required for the maintenance of genome stability. It is involved in the repair of DNA crosslinks, the resolution of recombination intermediates, the response to replication stress and the maintenance of telomere length. To carry out these diverse functions, SLX4 interacts with three structure-selective endonucleases, MUS81-EME1, SLX1 and XPF-ERCC1, as well as the telomere binding proteins TRF2, RTEL1 and SLX4IP. Recently, SLX4 was shown to interact with MutSβ, a heterodimeric protein involved in DNA mismatch repair, trinucleotide repeat instability, crosslink repair and recombination. Importantly, MutSβ promotes the pathogenic expansion of CAG/CTG trinucleotide repeats, which is causative of myotonic dystrophy and Huntington’s disease. The colocalization and specific interaction of MutSβ with SLX4, together with their apparently overlapping functions, are suggestive of a common role in reactions that promote DNA maintenance and genome stability. This review will focus on the role of SLX4 in DNA repair, the interplay between MutSβ and SLX4, and detail how they cooperate to promote recombinational repair and DNA crosslink repair. Furthermore, we speculate that MutSβ and SLX4 may provide an alternative cellular mechanism that modulates trinucleotide instability.

摘要

SLX4 为组装维持基因组稳定性所需的多种蛋白质复合物提供了分子支架。它参与 DNA 交联的修复、重组中间体的分解、对复制应激的反应和端粒长度的维持。为了执行这些不同的功能，SLX4 与三种结构选择性核酸内切酶 MUS81-EME1、SLX1 和 XPF-ERCC1，以及端粒结合蛋白 TRF2、RTEL1 和 SLX4IP 相互作用。最近，SLX4 被证明与 MutSβ 相互作用，MutSβ 是一种参与 DNA 错配修复、三核苷酸重复不稳定性、交联修复和重组的异二聚体蛋白。重要的是，MutSβ 促进 CAG/CTG 三核苷酸重复序列的致病性扩增，这是导致强直性营养不良和亨廷顿病的原因。MutSβ 与 SLX4 的共定位和特异性相互作用，以及它们明显重叠的功能，暗示了在促进 DNA 维持和基因组稳定性的反应中的共同作用。本综述将重点关注 SLX4 在 DNA 修复中的作用、MutSβ 和 SLX4 之间的相互作用，并详细说明它们如何合作促进重组修复和 DNA 交联修复。此外，我们推测 MutSβ 和 SLX4 可能提供另一种调节三核苷酸不稳定性的细胞机制。并详细说明他们如何合作促进重组修复和 DNA 交联修复。此外，我们推测 MutSβ 和 SLX4 可能提供另一种调节三核苷酸不稳定性的细胞机制。并详细说明他们如何合作促进重组修复和 DNA 交联修复。此外，我们推测 MutSβ 和 SLX4 可能提供另一种调节三核苷酸不稳定性的细胞机制。