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FLASH GENE

Symbol

LIG4

contributors: mct/npt - updated : 15-04-2015

HGNC name	ligase IV, DNA, ATP-dependent
HGNC id	6601

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

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 Cardiovascular heart       highly Digestive pharynx       highly Endocrine neuroendocrine pituitary     highly Hearing/Equilibrium ear       highly Lymphoid/Immune thymus         Reproductive male system testis         male system prostate       Respiratory respiratory tract trachea

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal part, spanning &
	8764;600 AAs, contains DNA-binding, adenylation and oligo-binding domains, which are thought important for ligase catalytic function
	a ligase domain
	C-terminal fragment of LIG4 (LIG4-CT), containing two BRCT (breast cancer associated 1 C-terminal) domains without N-terminal catalytic domains and could bind to chromatin with XRCC4

HOMOLOGY

interspecies

homolog to murine Lig4

Homologene

FAMILY

ATP-dependent DNA ligase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm

basic FUNCTION	the ligation responsible for DNA double-strand break repair by end joining (non homologous recombination NHEJ) and V(D)J recombination
	essential mammalian nonhomologous end joining protein used for V(D)J recombination and DNA repair (Wang 2004)
	DNA Ligase IV/XRCC4 recruited by PRKDC to DNA double-strand breaks prevents the formation of long single strand-DNA ends at double-strand breaks during the S phase (Karlsson 2007)
	prevents the joining of chromatide breaks into chromosome rearrangements in BRCA1-deficient cells (Bunting 2010)
	novel function of XRCC4 in controlling nuclear import and sub-nuclear distribution of LIG4, suggesting that XRCC4 modulates the dynamic interaction of the LIG4/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks
	is differentially required for certain chromosome fusion events induced by telomere dysfunction-used for those owing to the overexpression of a dominant negative version of TERC2
	LIG4 and RAD52 genes play important roles in DNA repair mechanisms
	LIG1 is not absolutely required for cellular DNA replication and repair and either LIG3 or LIG4 can substitute for the role of LIG1 in joining Okazaki fragments
	restoration of XRCC4 and LIG4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts

CELLULAR PROCESS	nucleotide, replication
	nucleotide, repair, recombination

PHYSIOLOGICAL PROCESS

development

text	neurogenesis
	lymphogenes

PATHWAY

metabolism

signaling

a component	complexing with XRCC4 and recruited by POLM to double strand break ends associated to DNA-dependent protein kinase (PRKDC)
	plays a critical role in the repair of DNA double-strand breaks

INTERACTION

DNA

binding

RNA

small molecule	nucleotide,
	ATP binding

protein	functionally linked with ERCC4 in the repair of double-stranded DNA breaks
	interacting with XRCC4 (XRCC4 bound to the carboxy-terminal tandem BRCT repeat of DNA ligase IV, and interaction with the second BRCT domain is necessary for stable binding to XRCC4 in cells, as well as to achieve efficient dominant-negative effects resulting in radiosensitization after ectopic overexpression of DNA LIG4 fragments in fibroblasts) (Wu 2009)
	XRCC4 modulates the dynamic interaction of the LIG4/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks
	DCLRE1C and LIG4 act cooperatively to promote Nonhomologous end-joining (NHEJ), thereby suppressing homologous recombination (HR) (PMI: 23967291)
	chromatin binding of XRCC4 was dependent on the presence of LIG4
	NHEJ1 is thought to stimulate the LIG4 activity toward incompatible or mismatched DNA ends

cell & other

REGULATION

repressed by

PRKDC (negatively regulate LIG4 protein stability) (Wang 2004)

ASSOCIATED DISORDERS

corresponding disease(s)

LIG4S

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in the bone marrow of adult myelodysplastic syndromes (Economopoulou 2010) tumoral     --low   by hypermethylation in colorectal cancer

Susceptibility

multiple myeloma to glioma

Variant & Polymorphism SNP	T91CT and T91TT protecting against multiple myeloma
	SNP increasing the risk of glioma

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS