CCAR2, also known as DBC1 (deleted in breast cancer 1), is a multifaceted protein involved in numerous biological processes. It acts as a master regulator of transcriptional processes and plays roles in apoptosis, DNA repair, metabolism, and tumorigenesis. CCAR2 functions as a coregulator of various transcription factors and a critical regulator of epigenetic modifiers. It is part of the 53BP1-RIF1 pathway which restricts DNA double-strand break (DSB) resection [1,2].

In gene knockout studies, knockout of CCAR2 in a BRCA1 -deficient cell line led to elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. This indicates that CCAR2 promotes blunt end-ligation by non-homologous end joining (NHEJ) repair, functioning downstream of the Shieldin complex [1]. In osteosarcoma cells, silencing CCAR2 prevented the malignant phenotype in vitro and decreased tumor growth in nude mice, suggesting its role in promoting cancer progression [3].

In conclusion, CCAR2 has diverse functions in regulating cell survival, DNA repair, and cancer development. Gene knockout models have been crucial in revealing its role in DNA repair processes, especially in the context of BRCA1 -deficient cells, and in cancer-related phenotypes such as in osteosarcoma. Understanding CCAR2 provides insights into the underlying mechanisms of DNA repair and cancer progression, potentially offering new therapeutic targets.

References:

1. Iyer, Divya Ramalingam, Harada, Naoya, Clairmont, Connor, Chowdhury, Dipanjan, D'Andrea, Alan D. 2022. CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2214935119. doi:10.1073/pnas.2214935119. https://pubmed.ncbi.nlm.nih.gov/36442094/

2. Kim, Hwa Jin, Moon, Sue Jin, Kim, Jeong Hoon. 2023. Mechanistic insights into the dual role of CCAR2/DBC1 in cancer. In Experimental & molecular medicine, 55, 1691-1701. doi:10.1038/s12276-023-01058-1. https://pubmed.ncbi.nlm.nih.gov/37524873/

3. Chen, Liang, Zhou, Shi-Jin, Xu, Yan, Zou, Yin-Shuang, Pei, Hong. 2021. CCAR2 promotes a malignant phenotype of osteosarcoma through Wnt/β-catenin-dependent transcriptional activation of SPARC. In Biochemical and biophysical research communications, 580, 67-73. doi:10.1016/j.bbrc.2021.09.070. https://pubmed.ncbi.nlm.nih.gov/34624572/