Ccar2-KO Mouse

Ccar2, also known as Deleted in breast cancer 1 (DBC1), is a master regulator of transcriptional processes, playing diverse roles in apoptosis, DNA repair, metabolism, and tumorigenesis. It functions as a coregulator of various transcription factors and a critical regulator of numerous epigenetic modifiers. Ccar2 is part of the 53BP1-RIF1 pathway which restricts DNA double-strand break (DSB) resection and promotes non-homologous end joining (NHEJ) repair [1,2].

Knockout of Ccar2 in a BRCA1-deficient cell line leads to elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance, indicating its role in suppressing homologous recombination. Ccar2 knockout cells also have delayed resolution of Shieldin complex foci, suggesting it functions downstream of the Shieldin complex [1]. In addition, CCAR2-deficient cells show perturbed mitotic progression, premature loss of cohesion with the centromere, and inactivation of the spindle assembly checkpoint, ultimately leading to activation of the abscission checkpoint to halt cytokinesis [3].

In summary, Ccar2 is crucial for multiple biological processes. Its role in DNA repair, as revealed by gene knockout models, is significant in understanding cancer development, especially in relation to PARPi resistance in BRCA1-deficient cells. Moreover, its function in regulating mitotic progression is vital for maintaining chromosomal stability [1,3].

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. Ryu, Jaewook, Kim, Ja-Eun. 2022. CCAR2 controls mitotic progression through spatiotemporal regulation of Aurora B. In Cell death & disease, 13, 534. doi:10.1038/s41419-022-04990-8. https://pubmed.ncbi.nlm.nih.gov/35672287/