Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France.
Inovarion, Paris, France.
Nat Struct Mol Biol. 2020 May;27(5):438-449. doi: 10.1038/s41594-020-0419-3. Epub 2020 May 11.
The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.
SLX4 肿瘤抑制因子是一种支架，在基因组保护的几个方面发挥关键作用，包括同源重组、链间 DNA 交联修复以及常见脆弱位点和端粒的维持。在这里，我们揭示了 SLX4 与 DNA 解旋酶 RTEL1 之间出人意料的直接相互作用，直到现在，这两种蛋白被认为具有独立和拮抗的功能。我们分别在 SLX4 和 RTEL1 中鉴定出与癌症和 Hoyeraal-Hreidarsson 综合征相关的突变，这些突变消除了 SLX4-RTEL1 复合物的形成。我们表明，这两种蛋白都被招募到新生 DNA 上，与活性 RNA pol II 紧密共定位，并且 SLX4 与 RTEL1 形成复合物可促进 FANCD2/RNA pol II 共定位。重要的是，破坏 SLX4-RTEL1 相互作用会导致未受应激的细胞中的 DNA 复制缺陷，而转录抑制可挽救这种缺陷。我们的数据表明，SLX4 和 RTEL1 相互作用以防止复制-转录冲突，并提供证据表明这与 SLX4 的核酶支架功能无关。
