Abstract
Fanconi anemia is a severe genetic disorder. Mutations in one of several genes lead to defects in DNA crosslink (CL) repair in human cells. An essential step in CL repair is the activation of the pathway by the monoubiquitination of the heterodimer FANCD2/FANCI, which recruits the nuclease FAN1 to the CL site. Surprisingly, FAN1 function is not conserved between different eukaryotes. No FAN1 homolog is present in Drosophila and Saccharomyces cerevisiae. The FAN1 homolog in Schizosaccharomyces pombe is involved in CL repair; a homolog is present in Xenopus but is not involved in CL repair. Here we show that a FAN1 homolog is present in plants and it is involved in CL repair in Arabidopsis thaliana. Both the virus-type replication-repair nuclease and the ubiquitin-binding ubiquitin-binding zinc finger domains are essential for this function. FAN1 likely acts upstream of two sub-pathways of CL repair. These pathways are defined by the Bloom syndrome homolog RECQ4A and the ATPase RAD5A, which is involved in error-free post-replicative repair. Mutations in both FAN1 and the endonuclease MUS81 resulted in greater sensitivity against CLs than in the respective single mutants. These results indicate that the two nucleases define two independent pathways of CL repair in plants.
Highlights
Fanconi anemia (FA) is an inherited disease in humans with symptoms such as bone marrow failure, congenital abnormalities and cancer
AtFAN1 has a length of 4382 bp between the start and stop codon; the gene is composed of 15 exons and 14 introns (Figure 1A)
To determine the evolutionary relationship between different FAN1 homologs, a phylogenetic tree was derived from a ClustalOmega multiple sequence alignment containing sequences of different FAN1 proteins from animals, plants and fungi
Summary
Fanconi anemia (FA) is an inherited disease in humans with symptoms such as bone marrow failure, congenital abnormalities and cancer. After the appearance of an interstrand CL, the FANC protein FANCM and its interacting partners MHF1, MHF2 and FAAP24 recognize and bind to the lesion This binding leads to the recruitment of the socalled FA core complex. The ID complex is recruited to the DNA damage site There, it facilitates the activation and recruitment of downstream FANC genes to repair the lesion. In addition to the FANC genes, several other FA-associated proteins have been described that are essential for CL repair [3,4] One of those FA-associated factors is the nuclease FAN1 (Fanconi/FANCD2 associated nuclease I), the recruitment of which is dependent on the monoubiquitination of FANCD2 [5,6,7,8].
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