The SLX4 protein is a multi-protein scaffold that coordinates the action of its partners in DNA repair mechanisms that maintain genome stability. It is known to be a tumor suppressor, meaning that when it is inactivated, the incidence of cancer increases. The team of PH Gaillard at CRCM/IPC in collaboration with the team of Patricia Kannouche at Gustave Roussy undertook the functional characterization of SLX4 mutations identified in metastatic tumors by the CRCM/IPC molecular oncology laboratory headed by Daniel Birnbaum and François Bertucci. They unraveled an unsuspected interaction between SLX4 and the RTEL1 DNA helicase enzyme that fulfils important genome maintenance functions. Mutations in SLX4 or RTEL1 that disrupt their interaction are observed in cancer and in patients with Hoyeraal–Hreidarsson syndrome. They went on to show that the SLX4-RTEL1 protein complex helps the cell overcome collisions between the DNA replication machinery and the RNA polymerase complex involved in gene expression and the transcription of other non-coding regions of the genome, allowing efficient duplication of the genetic material. This study reveals a novel function of SLX4 and opens new lines of investigation to figure out how it prevents the emergence of cancer and other human diseases.
SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations
Takedachi A, Despras E, Scaglione S, Guérois R, Guervilly JH, Blin M, Audebert S, Camoin L, Hasanova Z, Schertzer M, Guille A, Churikov D, Callebaut I, Naim V,Chaffanet M, Borg JP, Bertucci F, Revy P, Birnbaum D, Londoño-Vallejo A,
Kannouche PL and Gaillard PH
Nat Struct Mol Biol, 2020; VOL 27: 438–449