DNA repair protein XRCC4

Definition:

[DNA repair protein XRCC4]: DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination. Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed. XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity. Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Promotes displacement of PNKP from processed strand break termini.; [Protein XRCC4, C-terminus]: Acts as an activator of the phospholipid scramblase activity of XKR4. This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface.

References:

[1]. Sara N Andres, et al. A human XRCC4-XLF complex bridges DNA. Nucleic Acids Res. 2012 Feb;40(4):1868-78. [Content Brief]

[2]. S A Nick McElhinny, et al. Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol Cell Biol. 2000 May;20(9):2996-3003. [Content Brief]

[3]. Jiafeng Gu, et al. XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. EMBO J. 2007 Feb 21;26(4):1010-23. [Content Brief]

[4]. Ineke Brouwer, et al. Sliding sleeves of XRCC4-XLF bridge DNA and connect fragments of broken DNA. Nature. 2016 Jul 28;535(7613):566-9. [Content Brief]

[5]. Qiang Zhang, et al. FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. Mol Cell. 2016 Feb 4;61(3):419-433. [Content Brief]

[6]. Sunetra Roy, et al. XRCC4's interaction with XLF is required for coding (but not signal) end joining. Nucleic Acids Res. 2012 Feb;40(4):1684-94. [Content Brief]

[7]. Rebecca E Foster, et al. Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun. 2006 Mar 3;341(1):175-83. [Content Brief]

[8]. María A Recuero-Checa, et al. Electron microscopy of Xrcc4 and the DNA ligase IV-Xrcc4 DNA repair complex. DNA Repair (Amst). 2009 Dec 3;8(12):1380-9. [Content Brief]

[9]. Z Li, et al. The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell. 1995 Dec 29;83(7):1079-89. [Content Brief]

[10]. U Grawunder, et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature. 1997 Jul 31;388(6641):492-5. [Content Brief]

[11]. L Chen, et al. Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J Biol Chem. 2000 Aug 25;275(34):26196-205. [Content Brief]

[12]. R Daniel Aceytuno, et al. Structural and functional characterization of the PNKP-XRCC4-LigIV DNA repair complex. Nucleic Acids Res. 2017 Jun 2;45(10):6238-6251. [Content Brief]

[13]. Christine Anne Koch, et al. Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV. EMBO J. 2004 Oct 1;23(19):3874-85. [Content Brief]

[14]. Sunetra Roy, et al. XRCC4/XLF Interaction Is Variably Required for DNA Repair and Is Not Required for Ligase IV Stimulation. Mol Cell Biol. 2015 Sep 1;35(17):3017-28. [Content Brief]

[15]. Jae Wan Lee, et al. Requirement for XRCC4 and DNA ligase IV in alignment-based gap filling for nonhomologous DNA end joining in vitro. Cancer Res. 2003 Jan 1;63(1):22-4. [Content Brief]

[16]. Pierre-Olivier Mari, et al. Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18597-602. [Content Brief]

[17]. Masahiro Maruoka, et al. Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane. Mol Cell. 2021 Apr 1;81(7):1397-1410.e9. [Content Brief]

[18]. Mikoto Fukuchi, et al. Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear localization of XRCC4 and DNA ligase IV. Biochem Biophys Res Commun. 2015 Jun 12;461(4):687-94. [Content Brief]

[19]. Rajam S Mani, et al. Dual modes of interaction between XRCC4 and polynucleotide kinase/phosphatase: implications for nonhomologous end joining. J Biol Chem. 2010 Nov 26;285(48):37619-29. [Content Brief]

[20]. Elke Berg, et al. XRCC4 controls nuclear import and distribution of Ligase IV and exchanges faster at damaged DNA in complex with Ligase IV. DNA Repair (Amst). 2011 Dec 10;10(12):1232-42. [Content Brief]

[21]. Rujira Wanotayan, et al. Asparagine 326 in the extremely C-terminal region of XRCC4 is essential for the cell survival after irradiation. Biochem Biophys Res Commun. 2015 Feb 20;457(4):526-31. [Content Brief]

[22]. Christiaan de Bruin, et al. An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome. J Clin Endocrinol Metab. 2015 May;100(5):E789-98. [Content Brief]

[23]. Michal Hammel, et al. XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double strand break repair. J Biol Chem. 2011 Sep 16;286(37):32638-50. [Content Brief]

[24]. Virginie Ropars, et al. Structural characterization of filaments formed by human Xrcc4-Cernunnos/XLF complex involved in nonhomologous DNA end-joining. Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12663-8. [Content Brief]

[25]. Davide Normanno, et al. Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF C-terminal tails in modulating DNA bridging during classical non-homologous end joining. Elife. 2017 May 13;6:e22900. [Content Brief]

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