PRKDC
Description
The PRKDC (protein kinase, DNA-activated, catalytic subunit) is a protein-coding gene located on chromosome 8.
DNA-dependent protein kinase catalytic subunit, also known as DNA-PKcs, is an enzyme that plays a crucial role in repairing DNA double-strand breaks and has a number of other DNA housekeeping functions. In humans it is encoded by the gene designated as PRKDC or XRCC7. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase consisting of a single polypeptide chain of 4,128 amino acids.
== Function == DNA-PKcs is the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase called DNA-PK. The second component is the autoimmune antigen Ku. On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity. DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks. It is also required for V(D)J recombination, a process that utilizes NHEJ to promote immune system diversity. Many proteins have been identified as substrates for the kinase activity of DNA-PK. Autophosphorylation of DNA-PKcs appears to play a key role in NHEJ and is thought to induce a conformational change that allows end processing enzymes to access the ends of the double-strand break. DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.
PRKDC (DNA-PKcs) is a serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. It is crucial for DNA non-homologous end joining (NHEJ), a process essential for double-strand break (DSB) repair and V(D)J recombination. PRKDC requires DNA binding to exhibit its catalytic properties and promotes processing of hairpin DNA structures during V(D)J recombination through activation of the hairpin endonuclease artemis (DCLRE1C). Recruited by XRCC5 and XRCC6 to DNA ends, PRKDC plays a vital role in protecting and aligning broken DNA ends, preventing their degradation and sequestering the DSB for NHEJ-mediated repair. It also acts as a scaffold protein, facilitating the localization of DNA repair proteins to the site of damage. The assembly of the DNA-PK complex at DNA ends is essential for the NHEJ ligation step. Additionally, PRKDC is found at chromosome ends, suggesting a role in maintaining telomeric stability and preventing chromosomal end fusion. It is involved in transcriptional modulation and, as part of the DNA-PK complex, participates in the early steps of ribosome assembly by promoting the processing of precursor rRNA into mature 18S rRNA in the small-subunit processome. PRKDC interacts with U3 small nucleolar RNA, recruiting PRKDC and XRCC5/Ku86 to the small-subunit processome. Its substrate consensus sequence is [ST]-Q. PRKDC phosphorylates 'Ser-139' of histone variant H2AX, regulating DNA damage response mechanisms. It also phosphorylates a wide range of proteins, including ASF1A, DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, FH, SRF, NHEJ1/XLF, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC, and RFA2. PRKDC can phosphorylate C1D in the presence of linear or supercoiled DNA, and its ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. PRKDC contributes to circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, likely through an indirect mechanism. PRKDC plays a role in regulating DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, which serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. PRKDC also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, impairing CGAS oligomerization and activation, and by mediating phosphorylation of PARP1. DNA-PK is a heterotrimer composed of PRKDC and the Ku dimer (XRCC6/Ku70 and XRCC5/Ku86). Formation of this complex can be promoted by interaction with ILF3. PRKDC is part of the core long-range non-homologous end joining (NHEJ) complex, which includes PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86, and NHEJ1/XLF. Additional components of the NHEJ complex include PAXX. After autophosphorylation, PRKDC dissociates from DNA. PRKDC interacts with DNA-PKcs-interacting protein (KIP) in the region upstream of the kinase domain. PRKDC alone interacts with and phosphorylates DCLRE1C, activating the latent endonuclease activity of this protein. It interacts with C1D, TTI1, TELO2, CIB1, SETX, NR4A3, BRAT1, and KAT5. PRKDC is a component of the HDP-RNP complex, composed of HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3), and NEAT1 RNA.
PRKDC is also known as DNA-PKC, DNA-PKcs, DNAPK, DNAPKc, DNPK1, HYRC, HYRC1, IMD26, XRCC7, p350.
