XRCC4, or X-ray repair cross-complementing protein 4, is an essential molecule for the nonhomologous end joining (NHEJ) pathway, which is a major mechanism to repair DNA double-strand breaks (DSBs) [1,2,3,4,5,6,7,8,9]. NHEJ is crucial for maintaining genomic stability, and XRCC4's function in this pathway is of great biological importance. Genetic models, such as knockout mouse models, can be valuable for studying its function [9].

In XRCC4-deficient mouse embryos, they die before birth, highlighting its essential role in development [1]. In addition, mutations in XRCC4 in humans cause primordial dwarfism without overt immunodeficiency, despite the importance of NHEJ in V(D)J recombination during lymphocyte development [4]. Also, knockdown of XRCC4 in triple-negative breast cancer cells increases their radiosensitivity, indicating its potential as a target for radiotherapy [8].

In conclusion, XRCC4 is vital for the NHEJ-mediated repair of DNA double-strand breaks, which is crucial for genomic stability. Studies using XRCC4-deficient models, including those in mice and cell-based knockdown models, have revealed its role in development, primordial dwarfism, and cancer-related processes like radiosensitivity, providing insights into potential therapeutic strategies in cancer treatment.

References:

1. Tang, Jialin, Li, Zhongxia, Wu, Qiong, Li, Weili, Liu, Xiangyu. 2022. Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development. In Frontiers in immunology, 13, 852453. doi:10.3389/fimmu.2022.852453. https://pubmed.ncbi.nlm.nih.gov/35309348/

2. Koike, Manabu, Yutoku, Yasutomo, Koike, Aki. 2022. Feline XRCC4 undergoes rapid Ku-dependent recruitment to DNA damage sites. In FEBS open bio, 12, 798-810. doi:10.1002/2211-5463.13363. https://pubmed.ncbi.nlm.nih.gov/35000298/

3. Mahaney, Brandi L, Hammel, Michal, Meek, Katheryn, Tainer, John A, Lees-Miller, Susan P. 2013. XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair. In Biochemistry and cell biology = Biochimie et biologie cellulaire, 91, 31-41. doi:10.1139/bcb-2012-0058. https://pubmed.ncbi.nlm.nih.gov/23442139/

4. Saito, Shinta, Kurosawa, Aya, Adachi, Noritaka. 2016. Mutations in XRCC4 cause primordial dwarfism without causing immunodeficiency. In Journal of human genetics, 61, 679-85. doi:10.1038/jhg.2016.46. https://pubmed.ncbi.nlm.nih.gov/27169690/

5. Guo, Guijie, Gao, Ming, Gao, Xiaochen, Deng, Min, Lou, Zhenkun. 2021. Reciprocal regulation of RIG-I and XRCC4 connects DNA repair with RIG-I immune signaling. In Nature communications, 12, 2187. doi:10.1038/s41467-021-22484-7. https://pubmed.ncbi.nlm.nih.gov/33846346/

6. Yu, Yang, Sun, Yanyan, Li, Zhaoxian, Li, Jiang, Tian, Dazhi. 2023. Systematic analysis identifies XRCC4 as a potential immunological and prognostic biomarker associated with pan-cancer. In BMC bioinformatics, 24, 44. doi:10.1186/s12859-023-05165-8. https://pubmed.ncbi.nlm.nih.gov/36765282/

7. Wang, Shixin, Wu, Wangqiu, Liu, Yaxin, Li, Jingmin, Wang, Dong. 2023. Curcumin Induces Apoptosis by Suppressing XRCC4 Expression in Hepatocellular Carcinoma. In Nutrition and cancer, 75, 1958-1967. doi:10.1080/01635581.2023.2274132. https://pubmed.ncbi.nlm.nih.gov/37899756/

8. Wen, Yuqing, Dai, Gongpeng, Wang, Liping, Fu, Kanda, Zuo, Shuguang. 2019. Silencing of XRCC4 increases radiosensitivity of triple-negative breast cancer cells. In Bioscience reports, 39, . doi:10.1042/BSR20180893. https://pubmed.ncbi.nlm.nih.gov/30842344/

9. Benjamin, Ronald, Banerjee, Atoshi, Wu, Xiaogang, Pluth, Janice M, Schiller, Martin R. 2022. XRCC4 and MRE11 Roles and Transcriptional Response to Repair of TALEN-Induced Double-Strand DNA Breaks. In International journal of molecular sciences, 23, . doi:10.3390/ijms23020593. https://pubmed.ncbi.nlm.nih.gov/35054780/