UniProt functional annotation for P39748



	UniProt functional annotation for P39748

UniProt code: P39748.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Structure-specific nuclease with 5'-flap endonuclease and 5'- 3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site- terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA. {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:10744741, ECO:0000269|PubMed:11986308, ECO:0000269|PubMed:18443037, ECO:0000269|PubMed:20729856, ECO:0000269|PubMed:26751069, ECO:0000269|PubMed:7961795, ECO:0000269|PubMed:8621570}.

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Note=Binds 2 magnesium ions per subunit. They probably participate in the reaction catalyzed by the enzyme. May bind an additional third magnesium ion after substrate binding.;

Subunit: Three molecules of FEN1 bind to one PCNA trimer with each molecule binding to one PCNA monomer (PubMed:15616578). PCNA stimulates the nuclease activity without altering cleavage specificity (PubMed:15616578). The C-terminal domain binds EP300; can bind simultaneously to both PCNA and EP300 (PubMed:11430825). Interacts with PCNA; can bind simultaneously to both PCNA and EP300 (PubMed:9305916, PubMed:11430825). Interacts with DDX11; this interaction is direct and increases flap endonuclease activity of FEN1 (PubMed:18499658). Interacts with WDR4; regulating its endonuclease activity (PubMed:26751069). {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:11430825, ECO:0000269|PubMed:15616578, ECO:0000269|PubMed:18499658, ECO:0000269|PubMed:26751069, ECO:0000269|PubMed:9305916}.

Subcellular location: [Isoform 1]: Nucleus, nucleolus. Nucleus, nucleoplasm. Note=Resides mostly in the nucleoli and relocalizes to the nucleoplasm upon DNA damage.

Subcellular location: [Isoform FENMIT]: Mitochondrion {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:23675412}.

Ptm: Acetylated by EP300. Acetylation inhibits both endonuclease and exonuclease activity. Acetylation also reduces DNA-binding activity but does not affect interaction with PCNA or EP300. {ECO:0000255|HAMAP- Rule:MF_03140, ECO:0000269|PubMed:11430825}.

Ptm: Phosphorylation upon DNA damage induces relocalization to the nuclear plasma. Phosphorylation at Ser-187 by CDK2 occurs during late S-phase and results in dissociation from PCNA. {ECO:0000255|HAMAP- Rule:MF_03140, ECO:0000269|PubMed:20729856}.

Ptm: Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation and increases interaction with PCNA. {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:20729856}.

Miscellaneous: [Isoform FENMIT]: No nuclease activity. Binds preferentially to RNA flap structures and R-loops. {ECO:0000305}.

Similarity: Belongs to the XPG/RAD2 endonuclease family. FEN1 subfamily. {ECO:0000255|HAMAP-Rule:MF_03140}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Structure-specific nuclease with 5'-flap endonuclease and 5'- 3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site- terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA. {ECO:0000255\|HAMAP-Rule:MF_03140, ECO:0000269\|PubMed:10744741, ECO:0000269\|PubMed:11986308, ECO:0000269\|PubMed:18443037, ECO:0000269\|PubMed:20729856, ECO:0000269\|PubMed:26751069, ECO:0000269\|PubMed:7961795, ECO:0000269\|PubMed:8621570}.


Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Note=Binds 2 magnesium ions per subunit. They probably participate in the reaction catalyzed by the enzyme. May bind an additional third magnesium ion after substrate binding.;
Subunit:		Three molecules of FEN1 bind to one PCNA trimer with each molecule binding to one PCNA monomer (PubMed:15616578). PCNA stimulates the nuclease activity without altering cleavage specificity (PubMed:15616578). The C-terminal domain binds EP300; can bind simultaneously to both PCNA and EP300 (PubMed:11430825). Interacts with PCNA; can bind simultaneously to both PCNA and EP300 (PubMed:9305916, PubMed:11430825). Interacts with DDX11; this interaction is direct and increases flap endonuclease activity of FEN1 (PubMed:18499658). Interacts with WDR4; regulating its endonuclease activity (PubMed:26751069). {ECO:0000255\|HAMAP-Rule:MF_03140, ECO:0000269\|PubMed:11430825, ECO:0000269\|PubMed:15616578, ECO:0000269\|PubMed:18499658, ECO:0000269\|PubMed:26751069, ECO:0000269\|PubMed:9305916}.
Subcellular location:		[Isoform 1]: Nucleus, nucleolus. Nucleus, nucleoplasm. Note=Resides mostly in the nucleoli and relocalizes to the nucleoplasm upon DNA damage.
Subcellular location:		[Isoform FENMIT]: Mitochondrion {ECO:0000255\|HAMAP-Rule:MF_03140, ECO:0000269\|PubMed:23675412}.
Ptm:		Acetylated by EP300. Acetylation inhibits both endonuclease and exonuclease activity. Acetylation also reduces DNA-binding activity but does not affect interaction with PCNA or EP300. {ECO:0000255\|HAMAP- Rule:MF_03140, ECO:0000269\|PubMed:11430825}.
Ptm:		Phosphorylation upon DNA damage induces relocalization to the nuclear plasma. Phosphorylation at Ser-187 by CDK2 occurs during late S-phase and results in dissociation from PCNA. {ECO:0000255\|HAMAP- Rule:MF_03140, ECO:0000269\|PubMed:20729856}.
Ptm:		Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation and increases interaction with PCNA. {ECO:0000255\|HAMAP-Rule:MF_03140, ECO:0000269\|PubMed:20729856}.
Miscellaneous:		[Isoform FENMIT]: No nuclease activity. Binds preferentially to RNA flap structures and R-loops. {ECO:0000305}.
Similarity:		Belongs to the XPG/RAD2 endonuclease family. FEN1 subfamily. {ECO:0000255\|HAMAP-Rule:MF_03140}.