FIRRM, also known as C1orf112, is a crucial factor in maintaining genome stability. It is involved in DNA repair pathways, particularly homologous recombination (HR), by regulating the dynamics of RAD51, a core component of HR [1,2,4,5,6,7]. The FIRRM-FIGNL1 complex plays a significant role in processes such as resolving joint DNA molecules, preventing DNA damage-independent RAD51 and DMC1 loading, and disassembling RAD51-filaments during DNA repair and replication [1,2,5,7].

FIRRM deficiency in mice, demonstrated through KO/CKO mouse models, leads to various consequences. In male germline-specific conditional knock-out models, both FIGNL1 and FIRRM are required for completing meiotic prophase in mouse spermatocytes, with defective formation of late recombination intermediates in their absence [5]. In oocytes, deletion of FIRRM results in the formation of massive nuclear RAD51 foci, indicating substantial DNA damage and extensive HR. This leads to aberrant homologous chromosome segregation at metaphase I and primordial follicle insufficiency, rendering FIRRM-deleted females infertile [7]. In addition, FIRRM-deficient mice show early embryonic lethality and accelerated tumor formation, and FIRRM deficiency in cells causes hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S-G2 phase, and chromosomal aberrations [4].

In conclusion, FIRRM is essential for multiple biological processes related to genome stability, including meiotic recombination, DNA repair, and replication. Studies using KO/CKO mouse models have revealed its significant role in preventing tumorigenesis, maintaining oocyte genome integrity, and ensuring proper meiotic progression. These findings provide insights into the mechanisms of diseases associated with genome instability [4,5,7].

References:

1. Stok, Colin, Tsaridou, Stavroula, van den Tempel, Nathalie, Fehrmann, Rudolf S N, van Vugt, Marcel A T M. 2023. FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics. In Cell reports, 42, 112668. doi:10.1016/j.celrep.2023.112668. https://pubmed.ncbi.nlm.nih.gov/37347663/

2. Pinedo-Carpio, Edgar, Dessapt, Julien, Beneyton, Adèle, Fradet-Turcotte, Amélie, Orthwein, Alexandre. 2023. FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair. In Science advances, 9, eadf4082. doi:10.1126/sciadv.adf4082. https://pubmed.ncbi.nlm.nih.gov/37556550/

3. Tsaridou, Stavroula, van Vugt, Marcel A T M. 2024. FIRRM and FIGNL1: partners in the regulation of homologous recombination. In Trends in genetics : TIG, 40, 467-470. doi:10.1016/j.tig.2024.02.007. https://pubmed.ncbi.nlm.nih.gov/38494375/

4. Mazouzi, Abdelghani, Moser, Sarah C, Abascal, Federico, Jonkers, Jos, Brummelkamp, Thijn R. 2023. FIRRM/C1orf112 mediates resolution of homologous recombination intermediates in response to DNA interstrand crosslinks. In Science advances, 9, eadf4409. doi:10.1126/sciadv.adf4409. https://pubmed.ncbi.nlm.nih.gov/37256941/

5. Zainu, Akbar, Dupaigne, Pauline, Bouchouika, Soumya, Kumar, Rajeev, Baudat, Frédéric. 2024. FIGNL1-FIRRM is essential for meiotic recombination and prevents DNA damage-independent RAD51 and DMC1 loading. In Nature communications, 15, 7015. doi:10.1038/s41467-024-51458-8. https://pubmed.ncbi.nlm.nih.gov/39147779/

6. Zhou, Zenan, Yang, Han, Liang, Xinxin, Wang, Jiadong, Wang, Weibin. 2023. Reconstitution of the antagonistic effect between C1orf112/FIRRM-FIGNL1 and BRCA2 on RAD51 filament stabilization. In STAR protocols, 5, 102791. doi:10.1016/j.xpro.2023.102791. https://pubmed.ncbi.nlm.nih.gov/38133958/

7. Cao, Huiwen, Qiu, Cheng, Fang, Anxuan, Zhang, Qianting, Yu, Chao. . Extensive homologous recombination safeguards oocyte genome integrity in mammals. In Nucleic acids research, 53, . doi:10.1093/nar/gkae1304. https://pubmed.ncbi.nlm.nih.gov/39797737/