XRCC4 is a human gene whose product xLF (also known as NHEJ factor X or Cernunnos) is a core DNA non-homologous end joining (NHEJ) repair protein essential for V(D)J recombination and DSB repair[@ahnesorg2006]. The protein forms homodimers that bridge DNA ends and facilitates ligation by DNA-PKcs and XRCC4-LIG4 complex. Variants in XRCC4 have been implicated in Immunodeficiency, Cancer, Neurodegeneration. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
XLF (also known as NHEJ factor X or Cernunnos) is a core DNA non-homologous end joining (NHEJ) repair protein essential for V(D)J recombination and DSB repair[@ahnesorg2006]. The protein forms homodimers that bridge DNA ends and facilitates ligation by DNA-PKcs and XRCC4-LIG4 complex.
XRCC4 is a human gene whose product xLF (also known as NHEJ factor X or Cernunnos) is a core DNA non-homologous end joining (NHEJ) repair protein essential for V(D)J recombination and DSB repair[@ahnesorg2006]. The protein forms homodimers that bridge DNA ends and facilitates ligation by DNA-PKcs and XRCC4-LIG4 complex. Variants in XRCC4 have been implicated in Immunodeficiency, Cancer, Neurodegeneration. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
XLF (also known as NHEJ factor X or Cernunnos) is a core DNA non-homologous end joining (NHEJ) repair protein essential for V(D)J recombination and DSB repair[@ahnesorg2006]. The protein forms homodimers that bridge DNA ends and facilitates ligation by DNA-PKcs and XRCC4-LIG4 complex.
Key Molecular Functions
DNA end bridging: XLF homodimers tether blunt DNA ends together[@li2008]
V(D)J recombination: Essential for antigen receptor gene rearrangement in lymphocytes[@callebaut2006]
XRCC4-LIG4 recruitment: Directs ligase IV complex to DNA ends[@hentges2006]
Loop formation: Generates DNA loop structures facilitating repair[@lu2007]
XLF contains:
N-terminal globular head domain
C-terminal helical region
Dimerization interface
The XLF-XRCC4-LIG4 complex forms the "core" NHEJ machinery that ligates broken DNA ends[@lieber2010].
Disease Associations
Immunodeficiency
SCID with microcephaly: Biallelic XLF mutations cause severe combined immunodeficiency with growth retardation[@buck2006]
radiosensitive SCID: Cellular sensitivity to ionizing radiation[@du2008]
Cancer
Lymphoma: XLF variants in some B-cell malignancies[@liu2012]
Solid tumors: Altered expression in various cancers[@saito2011]
Neurodegeneration
Alzheimer's disease: NHEJ components dysregulated in AD [neurons](/entities/neurons); impaired DSB repair[@madsen2011]
Ataxia-telangiectasia: Overlapping phenotype with ATM deficiency[@stewart2009]