SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations
- 1 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 27 (5), 438-449
- https://doi.org/10.1038/s41594-020-0419-3
Abstract
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.Keywords
This publication has 76 references indexed in Scilit:
- Cooperative Control of Holliday Junction Resolution and DNA Repair by the SLX1 and MUS81-EME1 NucleasesMolecular Cell, 2013
- Landscape of transcription in human cellsNature, 2012
- RTEL1 contributes to DNA replication and repair and telomere maintenanceMolecular Biology of the Cell, 2012
- Mutations of the SLX4 gene in Fanconi anemiaNature Genetics, 2011
- Drosophila MUS312 and the Vertebrate Ortholog BTBD12 Interact with DNA Structure-Specific Endonucleases in DNA Repair and RecombinationMolecular Cell, 2009
- Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA RepairCell, 2009
- Human SLX4 Is a Holliday Junction Resolvase Subunit that Binds Multiple DNA Repair/Recombination EndonucleasesCell, 2009
- Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient ReplicationCell, 2009
- The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalitiesNature, 2009
- Jalview Version 2—a multiple sequence alignment editor and analysis workbenchBioinformatics, 2009