UniProt functional annotation for P12956



	UniProt functional annotation for P12956

UniProt code: P12956.

Organism: Homo sapiens (Human).

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

Function: Single-stranded DNA-dependent ATP-dependent helicase. Has a role in chromosome translocation. The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner. It works in the 3'-5' direction. Binding to DNA may be mediated by XRCC6. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The XRCC5/6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. The XRCC5/6 dimer is probably involved in stabilizing broken DNA ends and bringing them together. The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step. Required for osteocalcin gene expression. Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5- phosphate at an abasic site near double-strand breaks. 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined. The XRCC5/6 dimer together with APEX1 acts as a negative regulator of transcription. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. {ECO:0000269|PubMed:12145306, ECO:0000269|PubMed:20383123, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:2466842, ECO:0000269|PubMed:28712728, ECO:0000269|PubMed:7957065, ECO:0000269|PubMed:8621488, ECO:0000269|PubMed:9742108}.

Subunit: Heterodimer composed of XRCC5/Ku80 and XRCC6/Ku70. The dimer associates in a DNA-dependent manner with PRKDC to form the DNA- dependent protein kinase complex DNA-PK, and with the LIG4-XRCC4 complex to form the core of the non-homologous end joining (NHEJ) complex. Additional components of the NHEJ complex include NHEJ1/XLF and PAXX (PubMed:25574025, PubMed:25941166, PubMed:25670504). The dimer also associates with NAA15, and this complex binds to the osteocalcin promoter and activates osteocalcin expression. In addition, XRCC6 interacts with the osteoblast-specific transcription factors MSX2, RUNX2 and DLX5. Interacts with ELF3. Interacts with ATP23. The XRCC5/6 dimer associates in a DNA-dependent manner with APEX1. Binds to CDK9 isoform 2. Identified in a complex with DEAF1 and XRCC5. Interacts with DEAF1 (via the SAND domain); the interaction is direct and may be inhibited by DNA-binding (PubMed:10219089, PubMed:11493912, PubMed:12145306, PubMed:12509254, PubMed:12547193, PubMed:15075319, PubMed:20493174, PubMed:22442688, PubMed:8621488, PubMed:9742108). Interacts with CLU (By similarity). Interacts with NR4A3; the DNA- dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitinylation and degradation (PubMed:25852083). Interacts with CYREN isoform 1 (CYREN-1) and isoform 4 (CYREN-2) (PubMed:24610814, PubMed:28959974). Interacts (via N- terminus) with HSF1 (via N-terminus); this interaction is direct and prevents XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts with HMBOX1 (PubMed:23685356). Interacts with ATF7 (PubMed:29490055). {ECO:0000250|UniProtKB:P23475, ECO:0000269|PubMed:10219089, ECO:0000269|PubMed:11493912, ECO:0000269|PubMed:12145306, ECO:0000269|PubMed:12509254, ECO:0000269|PubMed:12547193, ECO:0000269|PubMed:15075319, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:22442688, ECO:0000269|PubMed:23685356, ECO:0000269|PubMed:24610814, ECO:0000269|PubMed:25574025, ECO:0000269|PubMed:25852083, ECO:0000269|PubMed:26359349, ECO:0000269|PubMed:28959974, ECO:0000269|PubMed:29490055, ECO:0000269|PubMed:8621488, ECO:0000269|PubMed:9742108}.

Subunit: (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ. {ECO:0000269|PubMed:29769340}.

Subcellular location: Nucleus {ECO:0000269|PubMed:22442688}. Chromosome {ECO:0000269|PubMed:22442688}.

Developmental stage: Expression does not increase during promyelocyte differentiation. {ECO:0000269|PubMed:8605992}.

Induction: In osteoblasts, by FGF2.

Ptm: Phosphorylation by PRKDC may enhance helicase activity. Phosphorylation of Ser-51 does not affect DNA repair. {ECO:0000269|PubMed:10026262, ECO:0000269|PubMed:12547193, ECO:0000269|PubMed:9362500}.

Ptm: ADP-ribosylated by PARP3. {ECO:0000269|PubMed:24598253}.

Miscellaneous: Individuals with systemic lupus erythematosus (SLE) and related disorders produce extremely large amounts of autoantibodies to XRCC5 and XRCC6. Existence of a major autoantigenic epitope or epitopes on the C-terminal 190 amino acids of XRCC6 containing the leucine repeat. The majority of autoantibodies to XRCC6 in most sera from patients with SLE seem to be reactive with this region.

Similarity: Belongs to the ku70 family. {ECO:0000305}.

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:		Single-stranded DNA-dependent ATP-dependent helicase. Has a role in chromosome translocation. The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner. It works in the 3'-5' direction. Binding to DNA may be mediated by XRCC6. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The XRCC5/6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. The XRCC5/6 dimer is probably involved in stabilizing broken DNA ends and bringing them together. The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step. Required for osteocalcin gene expression. Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5- phosphate at an abasic site near double-strand breaks. 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined. The XRCC5/6 dimer together with APEX1 acts as a negative regulator of transcription. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. {ECO:0000269\|PubMed:12145306, ECO:0000269\|PubMed:20383123, ECO:0000269\|PubMed:20493174, ECO:0000269\|PubMed:2466842, ECO:0000269\|PubMed:28712728, ECO:0000269\|PubMed:7957065, ECO:0000269\|PubMed:8621488, ECO:0000269\|PubMed:9742108}.


Subunit:		Heterodimer composed of XRCC5/Ku80 and XRCC6/Ku70. The dimer associates in a DNA-dependent manner with PRKDC to form the DNA- dependent protein kinase complex DNA-PK, and with the LIG4-XRCC4 complex to form the core of the non-homologous end joining (NHEJ) complex. Additional components of the NHEJ complex include NHEJ1/XLF and PAXX (PubMed:25574025, PubMed:25941166, PubMed:25670504). The dimer also associates with NAA15, and this complex binds to the osteocalcin promoter and activates osteocalcin expression. In addition, XRCC6 interacts with the osteoblast-specific transcription factors MSX2, RUNX2 and DLX5. Interacts with ELF3. Interacts with ATP23. The XRCC5/6 dimer associates in a DNA-dependent manner with APEX1. Binds to CDK9 isoform 2. Identified in a complex with DEAF1 and XRCC5. Interacts with DEAF1 (via the SAND domain); the interaction is direct and may be inhibited by DNA-binding (PubMed:10219089, PubMed:11493912, PubMed:12145306, PubMed:12509254, PubMed:12547193, PubMed:15075319, PubMed:20493174, PubMed:22442688, PubMed:8621488, PubMed:9742108). Interacts with CLU (By similarity). Interacts with NR4A3; the DNA- dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitinylation and degradation (PubMed:25852083). Interacts with CYREN isoform 1 (CYREN-1) and isoform 4 (CYREN-2) (PubMed:24610814, PubMed:28959974). Interacts (via N- terminus) with HSF1 (via N-terminus); this interaction is direct and prevents XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA (PubMed:28712728). Interacts with HMBOX1 (PubMed:23685356). Interacts with ATF7 (PubMed:29490055). {ECO:0000250\|UniProtKB:P23475, ECO:0000269\|PubMed:10219089, ECO:0000269\|PubMed:11493912, ECO:0000269\|PubMed:12145306, ECO:0000269\|PubMed:12509254, ECO:0000269\|PubMed:12547193, ECO:0000269\|PubMed:15075319, ECO:0000269\|PubMed:20493174, ECO:0000269\|PubMed:22442688, ECO:0000269\|PubMed:23685356, ECO:0000269\|PubMed:24610814, ECO:0000269\|PubMed:25574025, ECO:0000269\|PubMed:25852083, ECO:0000269\|PubMed:26359349, ECO:0000269\|PubMed:28959974, ECO:0000269\|PubMed:29490055, ECO:0000269\|PubMed:8621488, ECO:0000269\|PubMed:9742108}.
Subunit:		(Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ. {ECO:0000269\|PubMed:29769340}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:22442688}. Chromosome {ECO:0000269\|PubMed:22442688}.
Developmental stage:		Expression does not increase during promyelocyte differentiation. {ECO:0000269\|PubMed:8605992}.
Induction:		In osteoblasts, by FGF2.
Ptm:		Phosphorylation by PRKDC may enhance helicase activity. Phosphorylation of Ser-51 does not affect DNA repair. {ECO:0000269\|PubMed:10026262, ECO:0000269\|PubMed:12547193, ECO:0000269\|PubMed:9362500}.
Ptm:		ADP-ribosylated by PARP3. {ECO:0000269\|PubMed:24598253}.
Miscellaneous:		Individuals with systemic lupus erythematosus (SLE) and related disorders produce extremely large amounts of autoantibodies to XRCC5 and XRCC6. Existence of a major autoantigenic epitope or epitopes on the C-terminal 190 amino acids of XRCC6 containing the leucine repeat. The majority of autoantibodies to XRCC6 in most sera from patients with SLE seem to be reactive with this region.
Similarity:		Belongs to the ku70 family. {ECO:0000305}.