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Novel insights into the DNA interstrand cross-link repair in Schizosaccharomyces pombe: characterisation of Fan1 through standard and high-throughput genetic analysis

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posted on 2023-06-07, 16:13 authored by Yari Fontebasso
FAN1/MTMR15 (Fanconi anemia-associated nuclease 1 / Myotubularin-related protein 15) is a protein originally identified from a set of size-fractionated human brain cDNA libraries coding for large proteins in vitro (Nagase et al., 1999). FAN1 is widely conserved across eukaryotes, with the notable exception of S. cerevisiae (Smogorzewska et al., 2010; MacKay et al., 2010; Kratz et al., 2010; Liu et al., 2010; Shereda et al., 2010). Recent work has shown that FAN1 is a novel component of the Fanconi Anemia repair DNA pathway in higher eukaryotes (Smogorzewska et al., 2010; MacKay et al., 2010; Kratz et al., 2010; Yoshikiyo et al., 2010; Liu et al., 2010; Shereda et al., 2010). My work presents a biochemical and genetic characterisation of the FAN1 Schizosaccharomyces pombe ortholog Fan1. I show that, in contrast with the situation in higher eukaryotes, Fan1 in S. pombe does not strongly interact with components of the mismatch repair pathway. The disruption of fan1 causes a mild sensitivity to interstrand cross-linking agents, dramatically augmented by the concomitant deletion of the nuclease Pso2, suggesting a role for Fan1 in the resolution of DNA interstrand cross-links. Further genetic interactions are explored by use of an automated high-throughput screen, where a non-epistatic relationship is found with Pli1, a component of the SUMOylation pathway. Finally, I show that three conserved residues in the VRR_nuc nuclease domain are required for Fan1 activity in DNA repair. Taken together, the data presented points at a role for S. pombe Fan1 in the resolution of adducts created by DNA interstrand cross-linking agents.


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