DNA repair protein XRCC4

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DNA Repair Protein XRCC4

The DNA repair protein XRCC4 is a crucial component of the non-homologous end joining (NHEJ) pathway, which is one of the primary mechanisms for repairing double-strand breaks (DSBs) in DNA. These breaks can occur due to various factors, including ionizing radiation, oxidative stress, and during the process of V(D)J recombination in the immune system. XRCC4 plays a vital role in maintaining genomic stability and preventing mutations that could lead to cancer and other diseases.

Structure and Function

XRCC4 is a protein encoded by the XRCC4 gene located on chromosome 5 in humans. The protein itself is composed of several domains that facilitate its function in DNA repair. XRCC4 forms a complex with DNA Ligase IV, a critical enzyme that catalyzes the final ligation step in the NHEJ pathway. This complex is essential for the rejoining of DNA ends.

The XRCC4 protein has a coiled-coil domain that allows it to form homodimers or higher-order oligomers, which are necessary for its function in DNA repair. The C-terminal region of XRCC4 interacts with DNA Ligase IV, stabilizing the enzyme and enhancing its activity. Additionally, XRCC4 is known to interact with other proteins involved in the NHEJ pathway, such as Ku70/80 and Artemis, facilitating the recruitment and assembly of the repair complex at the site of DNA damage.

Role in Non-Homologous End Joining

In the NHEJ pathway, XRCC4 is recruited to the site of a DNA double-strand break by the Ku70/80 heterodimer, which binds to the DNA ends. XRCC4 then forms a complex with DNA Ligase IV, and together they perform the ligation of the DNA ends. This process is crucial for the repair of DSBs, especially in non-replicating cells where homologous recombination is not possible.

XRCC4 also plays a role in the processing of DNA ends to make them compatible for ligation. It is involved in the recruitment of Artemis, an endonuclease that processes DNA ends with overhangs or other complex structures. This processing is necessary to ensure that the DNA ends are suitable for ligation by DNA Ligase IV.

Clinical Significance

Mutations or deficiencies in XRCC4 can lead to severe consequences for cellular function and organismal health. Defects in XRCC4 are associated with increased sensitivity to ionizing radiation and a higher incidence of chromosomal translocations, which can lead to cancer. In particular, XRCC4 mutations have been linked to a rare condition known as LIG4 syndrome, characterized by immunodeficiency, microcephaly, and developmental delay.

Furthermore, XRCC4 is essential for the proper development of the immune system. During V(D)J recombination, which generates the diversity of antibodies and T-cell receptors, XRCC4 is required to join the coding ends of DNA segments. Deficiencies in XRCC4 can lead to severe combined immunodeficiency (SCID) due to the failure of lymphocyte development.

Research and Therapeutic Implications

Understanding the function and regulation of XRCC4 is critical for developing therapeutic strategies to enhance DNA repair in diseases characterized by genomic instability, such as cancer. Targeting the NHEJ pathway, and specifically XRCC4, could provide avenues for sensitizing cancer cells to radiation therapy or chemotherapy by inhibiting their ability to repair DNA damage.

Also see

• DNA Ligase IV
• Non-Homologous End Joining
• Ku70/80
• Artemis (protein)
• V(D)J recombination
• Chromosomal translocation