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FLASH GENE

Symbol

XRCC1

contributors: shn/npt/pgu - updated : 19-10-2018

HGNC name	X-ray repair complementing defective repair in Chinese hamster cells 1
HGNC id	12828

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006297 17 - 2102 NP_006288 69.3 633 - -

EXPRESSION

Type

widely

constitutive of

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 Nervous brain         Reproductive female system uterus cervix   highly Respiratory lung         Skin/Tegument skin       highly Visual eye       highly

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal domain (NTD) able to adopt a redox-dependent alternate fold, characterized by a disulfide bond, and binds to POLB
	a BRCT adaptor domain (BRCA1 C-terminus)
	two BRCT domains (BRCT1 and BRCT2) mediating a network of protein-protein interactions with several key factors of the DNA single-strand breaks (SSBs) and base damage repair pathways
	highly conserved REV1-interacting region (RIR) motif

mono polymer

monomer

HOMOLOGY

interspecies	ortholog to XRCC1, Pan troglodytes
	ortholog to Xrcc1, Mus musculus
	ortholog to XRCC1, Rattus norvegicus

Homologene

FAMILY

CATEGORY

DNA associated

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus

basic FUNCTION	activator of PNKP and DNA ligase III, involved in single-strand DNA break rejoining
	may be facilitating DNA strand break and base excision repair
	involved in the maintenance of genome stability
	having discrete G1 and S phase-specific functions
	together with APTX and PARP1, plays an essential role in single-strand DNA break repair
	required for efficient DNA single-strand breaks repair and genomic stability in human cells
	stimulates PNKP activity by displacing PNKP from the phosphorylated DNA product
	involved in the repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents
	critical scaffold protein that promotes efficient single-strand break repair by coordinating the enzymatic processing of nonconventional 3' or 5' DNA termini and single-strand break gaps
	protects against the lethality of induced oxidative DNA damage in nondividing neural cells
	recruiting ARL6IP5 to the DNA damage sites, that mediate the repair of DNA damage induced by oxidative stress via activating the expression of XRCC1 through MAPK-E2F1 signaling pathway and protecting XRCC1 from ubiquitin-proteasome degradation
	required for neurogenesis of cerebellar interneurons and for hippocampal homeostasis and prevention of neural DNA damage
	a crucial role in DNA repair pathway during the genesis of the nervous system and highlight cerebellar interneurons
	can stimulate PNKP by two independent mechanisms (stimulatory effect of phosphorylated XRCC1 on PNKP can be totally inhibited by the presence of excess FHA domain polypeptide, but non-phosphorylated XRCC1 is not susceptible to competition by the FHA domain)
	plays a central role in base excision repair (BER) and single strand break repair, coordinating the binding and activities of enzymes involved in the repair process
	functional role of XRCC1 in replication associated BER of uracil
	XRCC1, a LIG3-stabilizing cofactor, and LIG3 itself have been very widely assumed to provide major end-ligation functions in A-EJ (alternative end-joining)
	is dispensable for A-EJ during class switch recombination (CSR)
	possible involvement of XRCC1 and its associated repair factors in post replication repair
	has no inherent enzymatic activity, and is believed to function in base excision repair as a dedicated scaffold component that coordinates other DNA repair factors
	is without catalytic activity, but can interact with a number of known repair proteins
	key factor in single-strand break and base excision repair, is recruited into nuclear bodies formed in response to replication-related single-strand breaks

CELLULAR PROCESS

nucleotide, repair, base excision repair

PHYSIOLOGICAL PROCESS

nervous system

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA	exhibits preferential binding to DNA with single-strand breaks with a gap size of <5 nucleotides

RNA

small molecule

protein	polymerase (DNA directed)beta, POLB (
	DNA ligase III, LIG3 (
	poly (ADP-ribose) polymerase 1 , PARP1 (
	double-strand break (DSB) repair heterotrimeric complex DNA-PK in response to ionizing radiation provides the first evidence for their involvement in a common DSB repair pathway
	DNA POLB
	Poly(ADP-ribose) polymerase, PARP
	APEX nuclease (multifunctional DNA repair enzyme) 1, APEX1 (
	polynucleotide kinase phosphatase, PNKP
	BRCA1 carboxy terminal (
	Poly(ADP-ribose) polymerase-2, PARP2 (
	8-oxoguanine DNA glycosylase, OGG1
	Aprataxin, APTX (
	proliferating cell nuclear antigen, PCNA (
	DNA ligase 3 (DNL3), polynucleotide kinase 3'-phosphatase, and polymerase beta, ataxia with oculomotor apraxia type 1 (AOA) gene product aprataxin (
	Condensin I (
	tyrosyl-DNA phosphodiesterase 1, TDP1
	aprataxin and PNKP like factor, APLF (
	ADP-ribosylation-like factor 6 interacting protein 5, ARL6IP5 (may be required for XRCC1 stability)
	primase, DNA, polypeptide 2 (58kDa), PRIM2
	directly interacts with the nuclear localization signal-region (NLS) of XRCC1
	interaction of the XRCC1-derived peptide with REV1 C-terminal domain characterized by dissociation constants in the low micromolar range
	DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway
	in response to cellular proliferation and DNA damage, proteasome and HSP90AA1-mediated regulation of POLB and XRCC1 alters the DNA repair complex architecture
	chromatin remodeling factor SMARCA5 is a novel binding partner of XRCC1, with their interaction dependent on the casein kinase 2-mediated constitutive phosphorylation of XRCC1
	XRCC1 recruitment is promoted by PARP1, an enzyme that is activated following DNA damage and synthesizes ADP-ribose polymers that XRCC1 binds directly
	overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin
	interacts with multiple enzymes involved in DNA base excision repair and single-strand break repair (SSBR) and is important for genetic integrity and normal neurological function
	XRCC1 and PNKP interact via a high-affinity phosphorylation-dependent interaction site in XRCC1 and a forkhead-associated domain in PNKP
	repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CSNK2A2 at several consensus sites enables PNKP binding and recruitment to DNA damage
	XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity

cell & other

REGULATION

Other	phosphorylated by CHK2 and facilitating recruitment of downstream BER proteins to the initial damage recognition/excision step to promote Base Excision Repair
	regulated by ARL6IP5 under oxidative stress conditions

ASSOCIATED DISORDERS

corresponding disease(s)

SCAR26

Susceptibility

to squamous cell carcinoma of the head and neck and for tabacco and age related DNA damage to gastric cancer to breast cancer to glioma to testicular germ cell tumors to development of childhood ALL to systemic lupus erythematosus (SLE)

Variant & Polymorphism SNP , other	A194T increasing the risk of squamous cell carcinoma of the head and neck
	haplotype D (194Arg, 280Arg, and 399Arg alleles) is a risk type for gastric cancer
	polymorphisms at the codon 194 and 399 increasing the risk of breast cancer
	polymorphisms associated with the susceptibility and chromosomal aberration of testicular germ cell tumors
	may be associated with the progression of primary open-angle glaucoma in male patients of Pakistani origin (
	EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL
	XRCC1 Arg399Gln polymorphism might be associated with genetic susceptibility to SLE
	XRCC1 399Gln and 194Trp variants increase glioma risk

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Xrcc1 null mice are morphologically abnormal (increased cell death in the epiblast and an altered morphology in the visceral embryonic endoderm) and die around embryonic day 7
	mice with neural-specific inactivation of Xrcc1 exhibit profound neuropathology characterized by loss of cerebellar interneurons and persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function