Single-stranded DNA-dependent ATP-dependent helicase that plays a key role in DNA non-homologous end joining (NHEJ) by recruiting DNA-PK to DNA. Required for double-strand break repair and V(D)J recombination. Also 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. During NHEJ, the XRCC5-XRRC6 dimer performs the recognition step: it recognizes and binds to the broken ends of the DNA and protects them from further resection. Binding to DNA may be mediated by XRCC6. The XRCC5-XRRC6 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-XRRC6 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. The XRCC5-XRRC6 dimer 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. XRCC5 probably acts as the catalytic subunit of 5'-dRP activity, and 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-XRRC6 dimer together with APEX1 acts as a negative regulator of transcription. In association with NAA15, the XRCC5-XRRC6 dimer binds to the osteocalcin promoter and activates osteocalcin expression. As part of the DNA-PK complex, involved in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome. Binding to U3 small nucleolar RNA, recruits PRKDC and XRCC5/Ku86 to the small-subunit processome. 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. Heterodimer composed of XRCC5/Ku80 and XRCC6/Ku70 (By similarity). Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (By similarity). Additional component of the NHEJ complex includes PAXX (By similarity). Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (By similarity). The XRCC5-XRCC6 dimer also associates with NAA15, and this complex displays DNA binding activity towards the osteocalcin FGF response element (OCFRE) (By similarity). In addition, XRCC5 binds to the osteoblast-specific transcription factors MSX2 and RUNX2 (By similarity). Interacts with ELF3 (By similarity). Interacts with APLF (via KBM motif) (By similarity). The XRCC5/XRCC6 dimer associates in a DNA-dependent manner with APEX1 (By similarity). Identified in a complex with DEAF1 and XRCC6 (By similarity). Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitinylation and degradation (By similarity). Interacts with RNF138 (By similarity). Interacts with CYREN (via KBM motif) (PubMed:30017584). Interacts with WRN (via KBM motif) (By similarity). 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) (By similarity). Interacts with DHX9; this interaction occurs in a RNA-dependent manner (By similarity). 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 (By similarity). Interacts with ERCC6 (By similarity). Interacts with ATF7 (By similarity). The XRCC5-XRCC6 dimer associates with ALKBH2. Expression increases during promyelocyte differentiation. Up-regulation during myogenesis is inhibited by cAMP, 3-aminobenzamide and sodium butyrate. Expression in myoblasts is unaffected by X-rays and UV light. The EEXXXDDL motif is required for the interaction with catalytic subunit PRKDC and its recruitment to sites of DNA damage. ADP-ribosylated by PARP3. Phosphorylated on serine residues. Phosphorylation by PRKDC may enhance helicase activity. Sumoylated. Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination following DNA damage, leading to its degradation and removal from DNA damage sites. Ubiquitinated by RNF138, leading to remove the Ku complex from DNA breaks. Belongs to the ku80 family.