XRCC4
Description
The XRCC4 (X-ray repair cross complementing 4) is a protein-coding gene located on chromosome 5.
XRCC4, also known as X-ray repair cross-complementing protein 4, is a protein involved in DNA repair. It is a core factor in the non-homologous end joining (NHEJ) pathway, which repairs double-strand breaks (DSBs) in DNA. NHEJ requires two main components: the cooperative binding and phosphorylation of artemis by DNA-PKcs, which cleaves the ends of damaged DNA, and the bridging of DNA to DNA ligase 4 by XRCC4, with the aid of Cernunnos-XLF. XRCC4 is essential for the interaction of DNA ligase 4 with damaged DNA and subsequent ligation of the ends. Mutations in the XRCC4 gene can lead to embryonic lethality in mice and developmental inhibition and immunodeficiency in humans. Certain mutations are also linked to an increased risk of cancer. DSBs are primarily caused by free radicals generated from ionizing radiation and by-products of cellular metabolism.
XRCC4 is a key protein involved in non-homologous end joining (NHEJ), a major pathway for repairing double-strand breaks (DSBs) in DNA. It acts as a scaffold protein, recruiting other repair proteins to DSBs. XRCC4 forms complexes with NHEJ1/XLF, creating bridges that hold broken DNA fragments together. This bridging action helps stabilize the DNA fragments and ensures that the ends remain accessible for other repair factors. XRCC4 also plays a crucial role in the ligation step of NHEJ, directly interacting with DNA ligase IV (LIG4). The LIG4-XRCC4 complex reseals the DNA breaks after the gaps are filled. XRCC4 stabilizes LIG4, regulates its localization, and enhances its joining activity. The binding of the LIG4-XRCC4 complex to DNA ends depends on the assembly of the DNA-dependent protein kinase complex (DNA-PK) at these ends. Additionally, XRCC4 promotes the displacement of PNKP from processed strand break termini. XRCC4 is required for efficient DSB repair and is essential for normal development. Mutations in the XRCC4 gene can lead to developmental defects and increased cancer risk.
XRCC4 is also known as SSMED, hXRCC4.
Associated Diseases
- Microcephalic primordial dwarfism-insulin resistance syndrome
- LIG4 syndrome
- Short stature, microcephaly, and endocrine dysfunction
