DNA-dependent protein kinase catalytic subunit

Definition:

Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). Recruited by XRCC5 and XRCC6 to DNA ends and is required to (1) protect and align broken ends of DNA, thereby preventing their degradation, (2) and sequester the DSB for repair by NHEJ. Act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion (By similarity). Also involved in modulation of transcription. 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. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX, thereby regulating DNA damage response mechanism. Phosphorylates 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. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect mechanism (By similarity). 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. Also regulates the cGAS-STING pathway by catalyzing phosphorylation of CGAS, thereby impairing CGAS oligomerization and activation. Also regulates the cGAS-STING pathway by mediating phosphorylation of PARP1.

References:

[1]. T Carter, et al. A DNA-activated protein kinase from HeLa cell nuclei. Mol Cell Biol. 1990 Dec;10(12):6460-71. [Content Brief]

[2]. S Y Shieh, et al. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997 Oct 31;91(3):325-34. [Content Brief]

[3]. Hsin Ling Hsu, et al. Defining interactions between DNA-PK and ligase IV/XRCC4. DNA Repair (Amst). 2002 Mar 28;1(3):225-35. [Content Brief]

[4]. Xiaona Sun, et al. DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity. Nat Commun. 2020 Dec 3;11(1):6182. [Content Brief]

[5]. Siyu Chen, et al. Structural basis of long-range to short-range synaptic transition in NHEJ. Nature. 2021 May;593(7858):294-298. [Content Brief]

[6]. Yunmei Ma, et al. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol Cell. 2004 Dec 3;16(5):701-13. [Content Brief]

[7]. D W Chan, et al. DNA-dependent protein kinase phosphorylation sites in Ku 70/80 heterodimer. Biochemistry. 1999 Feb 9;38(6):1819-28. [Content Brief]

[8]. Zhengping Shao, et al. DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis. Nature. 2020 Mar;579(7798):291-296. [Content Brief]

[9]. Mukesh Kumar Sharma, et al. In cellulo phosphorylation of XRCC4 Ser320 by DNA-PK induced by DNA damage. J Radiat Res. 2016 Mar;57(2):115-20. [Content Brief]

[10]. Thomas Wechsler, et al. DNA-PKcs function regulated specifically by protein phosphatase 5. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1247-52. [Content Brief]

[11]. Nicolas Lévy, et al. XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage. Nucleic Acids Res. 2006 Jan 5;34(1):32-41. [Content Brief]

[12]. S Jin, et al. Double-strand break repair by Ku70 requires heterodimerization with Ku80 and DNA binding functions. EMBO J. 1997 Nov 17;16(22):6874-85. [Content Brief]

[13]. Y Ariumi, et al. Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene. 1999 Aug 12;18(32):4616-25. [Content Brief]

[14]. Yuhui Jiang, et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol. 2015 Sep;17(9):1158-68. [Content Brief]

[15]. U Yavuzer, et al. DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D. Genes Dev. 1998 Jul 15;12(14):2188-99. [Content Brief]

[16]. S Iijima, et al. DNA-activated protein kinase in Raji Burkitt's lymphoma cells. Phosphorylation of c-Myc oncoprotein. Eur J Biochem. 1992 Jun 1;206(2):595-603. [Content Brief]

[17]. Sébastien Soubeyrand, et al. Threonines 2638/2647 in DNA-PK are essential for cellular resistance to ionizing radiation. Cancer Res. 2003 Mar 15;63(6):1198-201. [Content Brief]

[18]. Tarren Reitsema, et al. DNA-PK is responsible for enhanced phosphorylation of histone H2AX under hypertonic conditions. DNA Repair (Amst). 2005 Sep 28;4(10):1172-81. [Content Brief]

[19]. Ali Reza Amiri Moghani, et al. In cellulo phosphorylation of DNA double-strand break repair protein XRCC4 on Ser260 by DNA-PK. J Radiat Res. 2018 Nov 1;59(6):700-708. [Content Brief]

[20]. Fei Wang, et al. Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS. Mol Cell. 2022 Jun 2;82(11):2032-2049.e7. [Content Brief]

[21]. Yaping Yu, et al. DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for repair of DNA double strand breaks. DNA Repair (Amst). 2008 Oct 1;7(10):1680-92. [Content Brief]

[22]. Yaping Yu, et al. DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Repair (Amst). 2003 Nov 21;2(11):1239-52. [Content Brief]

[23]. Mehdi Morchikh, et al. HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response. Mol Cell. 2017 Aug 3;67(3):387-399.e5. [Content Brief]

[24]. Eun-Jung Park, et al. DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner. Nucleic Acids Res. 2003 Dec 1;31(23):6819-27. [Content Brief]

[25]. A J Bannister, et al. c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro; definition of the minimal kinase recognition motif. Nucleic Acids Res. 1993 Mar 11;21(5):1289-95. [Content Brief]

[26]. S H Liu, et al. The carboxyl-terminal transactivation domain of human serum response factor contains DNA-activated protein kinase phosphorylation sites. J Biol Chem. 1993 Oct 5;268(28):21147-54. [Content Brief]

[27]. Yunmei Ma, et al. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002 Mar 22;108(6):781-94. [Content Brief]

[28]. Suisheng Zhang, et al. DNA-dependent protein kinase (DNA-PK) phosphorylates nuclear DNA helicase II/RNA helicase A and hnRNP proteins in an RNA-dependent manner. Nucleic Acids Res. 2004 Jan 2;32(1):1-10. [Content Brief]

[29]. Kyung-Jong Lee, et al. Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of mutations at these sites on DNA end joining in a cell-free system. DNA Repair (Amst). 2004 Mar 4;3(3):267-76. [Content Brief]

[30]. Ting-Hsiang Huang, et al. The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Mol Cell. 2018 Mar 1;69(5):879-892.e5. [Content Brief]

[31]. Parimal Karmakar, et al. Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation. J Biol Chem. 2002 May 24;277(21):18291-302. [Content Brief]

[32]. Caroline Schild-Poulter, et al. Down-regulation of histone H2B by DNA-dependent protein kinase in response to DNA damage through modulation of octamer transcription factor 1. Cancer Res. 2003 Nov 1;63(21):7197-205. [Content Brief]

[33]. S P Lees-Miller, et al. The human double-stranded DNA-activated protein kinase phosphorylates the 90-kDa heat-shock protein, hsp90 alpha at two NH2-terminal threonine residues. J Biol Chem. 1989 Oct 15;264(29):17275-80. [Content Brief]

[34]. H Niu, et al. Mapping of amino acid residues in the p34 subunit of human single-stranded DNA-binding protein phosphorylated by DNA-dependent protein kinase and Cdc2 kinase in vitro. J Biol Chem. 1997 May 9;272(19):12634-41. [Content Brief]

Biomedical Dictionary

The Biomedical Dictionary is a comprehensive and professional collection of biological academic terms and subject datas. All explanations are supported by authoritative books or high impact factor literatures, and you can acquire accurate explanations of the biomedical terms you want to know.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z #

Name
Email *

	Sorry, but the email address you supplied was invalid.