XRCC4, short for X-ray repair cross-complementing protein 4, is an essential molecule in the non-homologous end joining (NHEJ) pathway, which is a major mechanism for repairing DNA double-strand breaks (DSBs) [1-4, 6-8]. DSBs are highly cytotoxic forms of DNA damage, and XRCC4's role in NHEJ is crucial for maintaining genomic stability and cell survival. It interacts with DNA ligase IV, stabilizing it, and also with XRCC4-like factor (XLF) to form long helical protein filaments that protect and align DNA ends for ligation and repair [2].

Mutations in XRCC4 have been identified as the cause of primordial dwarfism without causing immunodeficiency, despite NHEJ being essential for V(D)J recombination during lymphocyte development [1]. In addition, studies on cell lines with XRCC4 knockout showed that TALEN-induced DSBs can still be repaired, although with reduced efficiency, and unique transcriptional responses were observed, including changes in p53 downstream pathways and metabolic pathways [5]. In cancer research, XRCC4 expression is significantly upregulated in 15 tumor types and downregulated in two compared to normal tissues. High XRCC4 expression is associated with poor prognosis in some cancers, and curcumin can induce apoptosis in hepatocellular carcinoma by suppressing XRCC4 expression [3,4]. Also, silencing XRCC4 increases the radiosensitivity of triple-negative breast cancer cells, and XRCC4 c.1394G>T polymorphism may be associated with breast cancer development among Filipinos [6,7].

In conclusion, XRCC4 is vital for DNA double-strand break repair through its role in the NHEJ pathway. Research using knockout models and studies on cancer cells has revealed its significance in diseases such as primordial dwarfism and various cancers. Understanding XRCC4's function provides insights into disease mechanisms and potential therapeutic targets, especially in cancer treatment, where its regulation could impact radiosensitivity and tumor progression.