Non-homologous end-joining factor 1

Definition:

DNA repair protein involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination. Plays a key role in NHEJ by promoting the ligation of various mismatched and non-cohesive ends. Together with PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends. May act in concert with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are non-complementary or partially complementary. Associates with XRCC4 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. Binds DNA in a length-dependent manner.

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]. Sara N Andres, et al. Crystal structure of human XLF: a twist in nonhomologous DNA end-joining. Mol Cell. 2007 Dec 28;28(6):1093-101. [Content Brief]

[3]. 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]

[4]. Andrew Craxton, et al. PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair. Nat Commun. 2018 Sep 24;9(1):3877. [Content Brief]

[5]. 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]

[6]. Enriqueta Riballo, et al. XLF-Cernunnos promotes DNA ligase IV-XRCC4 re-adenylation following ligation. Nucleic Acids Res. 2009 Feb;37(2):482-92. [Content Brief]

[7]. Chun J Tsai, et al. Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc Natl Acad Sci U S A. 2007 May 8;104(19):7851-6. [Content Brief]

[8]. Peter Ahnesorg, et al. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell. 2006 Jan 27;124(2):301-13. [Content Brief]

[9]. Haihui Lu, et al. Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J Biol Chem. 2007 Apr 13;282(15):11155-62. [Content Brief]

[10]. Laurent Malivert, et al. Delineation of the Xrcc4-interacting region in the globular head domain of cernunnos/XLF. J Biol Chem. 2010 Aug 20;285(34):26475-83. [Content Brief]

[11]. Mengtan Xing, et al. Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway. Nat Commun. 2015 Feb 11;6:6233. [Content Brief]

[12]. Dietke Buck, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006 Jan 27;124(2):287-99. [Content Brief]

[13]. 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]

[14]. 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]

[15]. 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]

[16]. 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]

[17]. Jiafeng Gu, et al. Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. Nucleic Acids Res. 2007;35(17):5755-62. [Content Brief]

[18]. 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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