This entry includes a group of nucleases from bacteria and eukaryotes, including fanconi-associated nuclease 1 (Fan1) from eukaryotes. Fan1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks (ICLs). It is the only VRR-Nuc-domain-containing protein in eukaryotes. It acts as a 5'-3' exonuclease that anchors at a cut end of DNA and cleaves DNA successively at every third nucleotide, allowing to excise an ICL from one strand through flanking incisions [].The Fan1 bacterial homologue, such as Pseudomonas aeruginosa FAN1 (PaFAN1), also exhibits a strong preference for 5' flap and nicked DNA [].
The Fanconi Anemia (FA) pathway is responsible for interstrand crosslink DNA repair []. The name originates the recessive syndrome known as Fanconi anemia, which causes developmental problems and cancer predisposition []. In this pathway, the FANCI-FANCD2 (ID) complex is ubiquitinated by the FA core complex and then travels to sites of damage to coordinate repair [, ]. FA pathway activation seems to trigger dissociation of FANCD2 from FANCI, coinciding with FANCD2 monoubiquitination which precedes monoubiquitination of FANCI []. This suggests a functional separation for FANCD2 from FANCI [].Monoubiquitinated FANCD2 functions to recruit DNA repair factors FAN1 (Fanconi-associated nuclease 1) []and SLX4 [], suggesting that chromatin-bound FANCD2Ub is a docking platform for certain DNA repair nucleases. FANCD2 has also a role in replication fork recovery [].
This domain is found in Fanconi-anemia-associated nuclease 1 (FAN1) present in Pseudomonas aeruginosa. FAN1 is a nuclease associated with Fanconi anemia (FA), an autosomal recessive genetic disorder caused by defects in FA genes responsible for processing DNA inter-strand cross-links (ICLs). The domain, known as the SAP domain, helps to augment the overall protein DNA interaction by interacting with the 3' and 5' ends of the template strand. Support of the pre-nick segment binding is crucial as multiple mutations in this domain resulted in hypersensitivity to a cross-linking agent in the SAP domain of Caenorhabditis elegans' FAN1. The helix-hairpin-helix of the SAP recognize three consecutive phosphate groups (C19, A20 and A21) at the 3' end of the template via the basic residues K116, K135 and K117 [].
