期刊
DNA REPAIR
卷 12, 期 12, 页码 1011-1023出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2013.10.003
关键词
ICL; Genetic screen; Synthetic array; Epistasis; Schizosaccharomyces pombe; Cisplatin
资金
- Medical Research Council [G1100074]
- ERC [268788-SMI-DDR]
- Cancer Research UK [14532] Funding Source: researchfish
- Medical Research Council [G1100074, G0500308] Funding Source: researchfish
- MRC [G1100074, G0500308] Funding Source: UKRI
DNA interstrand cross-links (ICLs) represent a physical barrier to the progression of cellular machinery involved in DNA metabolism. Thus, this type of adduct represents a serious threat to genomic stability and as such, several DNA repair pathways have evolved in both higher and lower eukaryotes to identify this type of damage and restore the integrity of the genetic material. Human cells possess a specialized ICL-repair system, the Fanconi anemia (FA) pathway. Conversely yeasts rely on the concerted action of several DNA repair systems. Recent work in higher eukaryotes identified and characterized a novel conserved FA component, FAN1 (Fanconi anemia-associated nuclease 1, or FANCD2/FANCI-associated nuclease 1). In this study, we characterize Fan1 in the yeast Schizosaccharomyces pombe. Using standard genetics, we demonstrate that Fan1 is a key component of a previously unidentified ICL-resolution pathway. Using high-throughput synthetic genetic arrays, we also demonstrate the existence of a third pathway of ICL repair, dependent on the SUMO E3 ligase Pli1. Finally, using sequence-threaded homology models, we predict and validate key residues essential for Fan1 activity in ICL repair. (C) 2013 Published by Elsevier B.V.
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