In silico analysis of several frequent SLX4 mutations appearing in human cancers

Abstract

SLX4 is an interactor and activator of structure-specific exonuclease that helps resolve tangled recombination intermediates arising at stalled replication forks. It is one of the many factors that assist with homologous recombination, the major mechanism for restarting replication. SLX4 mutations have been reported in many cancers but a pan cancer map of all the mutations has not been undertaken. Here, using data from the Catalogue of Somatic Mutations in Cancers (COSMIC), we show that mutations occur in almost every cancer and many of them truncate the protein which should severely alter the function of the enzyme. We identified a frequent R1779W point mutation that occurs in the SLX4 domain required for heterodimerization with its partner, SLX1. In silico protein structure analysis of this mutation shows that it significantly alters the protein structure and is likely to destabilize the interaction with SLX1. Although this brief communication is limited to only in silico analysis, it identifies certain high frequency SLX4 mutations in human cancers that would warrant further in vivo studies. Additionally, these mutations may be potentially actionable for drug therapies.

Figure 1. Pan-cancer analysis of SLX4 mutations

A . SLX4 mutations in all cancers are primarily coding. B . A map of SLX4 showing the relevant domains. The diagram was adapted from (Payliss et al., 2021). Shown on the diagram are truncating mutations (black) and high frequency mutations (>5) in red. C . Distribution of coding mutations (silent, missense, nonsense, InDel) by cancer type. D. (Top) Model showing location of WT R1779 residue (orange) interacting with the side chain of E1816 (yellow) through a salt-bridge (shown in dashed magenta lines). (Bottom) A model of the W1779 (orange) mutation with the loss of the E1816 (yellow) salt-bridge interaction. E . (Top) Electrostatic surface potential of the WT protein where the location of the R1779 is circled. (Bottom) Electrostatic surface potential of the R1779W mutant where the location of the W1779 residue is circled. Blue represents a basic or positive charge, red is an acidic or negative charge, white is neutral.