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FLASH GENE

Symbol

FEN1

contributors: shn/pgu - updated : 09-09-2015

HGNC name	flap structure-specific endonuclease 1
HGNC id	3650

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	4.56 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D11S1765 - D11S4076 - FEN1 - D11S4205 - D11S1883 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004111 2 - 2265 NP_004102 42.4 380 - 1995 7774922 FENMIT - initiation site - - - localizes to mitochondria 2013 23675412 truncated FEN1 isoform with a mitochondrial targeting signal can bind to R-loops, and to a lesser extent to D-loops likely interacts with RNA/DNA hybrids in mitochondrial DNA, such as those found at the origin of replication

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine       Reproductive female system breast mammary gland       female system uterus cervix   highly Respiratory lung         Urinary bladder       highly Visual eye

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		basic
STRUCTURE

motifs/domains	a N terminal flexible loop required for cleavage
	a catalytic site
	a DNA-binding motif
	C-terminal domain implicated in re-initiation of stalled replication forks , and with the nuclease domain of are involved in interaction with TERT, whereas the PCNA binding ability of FEN1 is dispensable for the interaction

HOMOLOGY

interspecies	homolog to rad27, Saccharomyces cerevisiae
	ortholog to Fen1, Rattus norvegicus
	ortholog to Fen1, Mus musculus

Homologene

FAMILY	XPG/RAD2 endonuclease family
	FEN1 subfamily

CATEGORY

enzyme , DNA associated

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,telomere
	intracellular,nucleus,nucleolus
text	colocalize in the nucleus with NEIL1
	localizes to the mammalian telomere
	RECQL and FEN1 were constitutively present at telomeres and their binding to the telomeric chromatin was enhanced following DNA damage

basic FUNCTION	essential for cell-free DNA replication
	involved in long patch base excision repair, DNA replication, where it processes Okazaki fragments, recombination and repair where it interacts with PCNA complex and DNA and acts as an exonuclease
	playing a role in transcription and elongation
	has a role in multiple DNA metabolic pathways and critical role in maintaining the integrity of the genome
	FEN1-WRN complex has an important role in DNA metabolism
	plays an important role in DNA replication,repair and recombination
	important for processing DNA ends during homologous recombination
	plays a vital role in maintaining genome stability
	can regulate telomerase activity at telomeres in mammalian cells
	might be required for telomerase-mediated telomere maintenance
	role in repairing mitochondrial oxidative DNA damage
	contributing to telomere stability and integrity in cells that rely on the alternative lengthening of telomere mechanism
	could participate in strand displacement repair synthesis (long patch repair LP-BER) mediated by FEN1 and stimulated by PCNA and strongly implicated in a distinct subpathway of LP-BER in replicating genomes
	structure-specific endonuclease that plays an important role in DNA metabolism
	required for replication of lagging strand telomeres
	maintains stable telomeres by facilitating replication through the G-rich lagging strand telomere, thereby ensuring high fidelity telomere replication
	promotes efficient re-initiation of stalled replication forks
	necessary for efficient replication of telomeres, and potentially promotes replication fork re-initiation within telomeric sequences
	important guardian of genome stability, and major player in telomere maintenance
	FEN1 and TERT complex could be participating in crucial events at telomeres and understanding the role of this complex can pave way for telomerase based cancer therapeutics
	FEN1, EXO1, ERCC5, and GEN1 are junction specific enzymes that require three separate binding sites for DNA and that incise one base pair into the duplex region of the substrate
	cell-cycle-dependent timing of FEN1 nuclease activity is essential for cell-cycle progression and the maintenance of genome stability
	plays an essential role in keeping genomic instability and preventing tumorigenesis
	conserved collaboration of RECQL with FEN1, suggesting both overlapping and specialized roles of RECQL in the processing of DNA structure intermediates proposed to arise during replication, repair and recombination
	canonical lagging strand DNA replication protein, required for normal, complete leading strand replication at telomeres
	removes flaps containing trinucleotide repeats (TNR) sequences at a rate slower than mixed sequence flaps of the same length

CELLULAR PROCESS	nucleotide, replication
	nucleotide, repair, base excision repair
	nucleotide, genomic integrity

PHYSIOLOGICAL PROCESS

text	maintenance of genomic stability

PATHWAY

metabolism

signaling

removes 5' overhanging flaps in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis

a component	complexing with PCNA
	FEN1 forms a complex with telomerase in a cell cycle dependent manner
	EXO1, ERCC5, and GEN1, whose activities span multiple DNA repair pathways, are members of the 5 prime nuclease superfamily with FEN1

INTERACTION

DNA	telomeric DNA

RNA

small molecule

protein	(RFC1) complex stimulates the nuclease activity of human FEN1 in an ATP-independent manner
	PCNA(to promote the coordination of enzymatic activities during DNA replication and repair), but this interaction is dispensable for its role at the telomere
	WRN stimulating FEN1 cleavage
	AP endonuclease 1
	Cyclin dependent kinase 2
	E1A binding protein p300
	HNRNPA1
	RecQ protein like 2 (WRN)
	RecQ helicase-like (BLM)
	telomerase (catalytic subunit hTERT)
	telomere-binding proteins TRF2
	with FEN1, DNA2 is thought to be involved in the repair of oxidative lesions in DNA molecules
	co-localizes to stalled replication forks where it interacts with the RecQ helicase, WRN, and is postulated to re-initiate stalled DNA replication forks
	FEN1 and telomerase association occurs throughout the S phase, with the maximum association in the mid S phase
	both MUS81-EME1 and MUS81-EME2 increased the activity of FEN1, but FEN1 did not stimulate the activity of MUS81-EME1/EME2
	FANCA, a protein that recognizes 5' flap structures and is involved in DNA repair and maintenance of replication forks, constantly stimulates FEN1-mediated incision of both DNA and RNA flaps
	regulation of FEN1 by FANCA contributes to the maintenance of genomic stability
	WDR4-FEN1 interaction may have a critical role in the growth and development, and in the maintenance of genome stability

cell & other

REGULATION

activated by	PCNA (prolifering cell nuclear antigen)
	WRN (Werner syndrome protein)
	acetylated by the transcriptional coactivator EP300
	APE1 stimulates FFEN1 and coordinates FEN1 and LIG1 in B long patch BER
	HIV-1 Integrase

Other

FEN1 phosphorylation stimulated its SUMOylation, which in turn stimulated its ubiquitination and ultimately led to its degradation via the proteasome pathway

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       mutated in Cockayne syndrome, severe form tumoral     --over   in lung cancer tumoral somatic mutation       abrogated two of three nuclease activities of flap endonuclease 1 in several cancer

Susceptibility

to developing breast cancer to glioma

Variant & Polymorphism SNP	FEN1-69GG genotypes were significantly correlated to increased risk for developing breast cancer compared with the -69AA genotype
	FEN1-69GG or 4150GG genotype were significantly associated to increased glioma risk

Candidate gene
Marker	is a promising biomarker in breast and ovarian epithelial cancer
Therapy target

ANIMAL & CELL MODELS

Fen1 depleted null mice showed embryonic lethality and the blastocysts displayed proliferation failure and increased sensitivity to gamma radiation