Fam72a, a poorly characterized yet evolutionarily conserved gene across multicellular organisms, plays diverse crucial roles [2]. It is involved in regulating the cell cycle and apoptosis, and has a significant impact on antibody maturation and DNA repair pathways. Functionally, it directly binds to tubulin and subunits of PP2A-B56, modulating phosphorylation events that affect cell cycle progression and apoptosis signaling [2]. In the context of antibody maturation, it is a key determinant for the error-prone processing of deoxyuracils, interacting with UNG2 to promote mutagenic repair [1,3,4].

Genetic models, especially Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/-mice, have revealed its importance. These cells exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, along with reduced genome-wide deoxyuracils [1,3]. In cancer research, overexpression of Fam72a is observed in many cancers, potentially promoting mutagenesis and tumorigenesis. For instance, in glioma, it promotes tumor progression by regulating mitophagy through the Pink1/Parkin signaling pathway and tumor immune escape by upregulating PD-L1 expression [5]. In hepatocellular carcinoma, high FAM72A expression is associated with a poor prognosis, and knockdown suppresses cell proliferation [6]. In multiple myeloma, overexpression of FAM72A promotes cell proliferation, inhibits apoptosis, and reduces sensitivity to bortezomib by regulating the POU2F2/FAM72A/p53 signaling pathway [7].

In conclusion, Fam72a is a multifunctional gene. Its role in the cell cycle, apoptosis, antibody maturation, and DNA repair has been elucidated through model-based research. The use of Fam72a-/-mouse models has been instrumental in understanding its contribution to various disease areas, including cancer, providing potential therapeutic targets for these diseases.

References:

1. Feng, Yuqing, Li, Conglei, Stewart, Jessica A, Bhagwat, Ashok S, Martin, Alberto. 2021. FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation. In Nature, 600, 324-328. doi:10.1038/s41586-021-04144-4. https://pubmed.ncbi.nlm.nih.gov/34819670/

2. Fu, Yuan, Jia, Xiaofan, Yuan, Jinwei, Zhou, Jun, Wang, Ting. 2023. Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates. In Developmental cell, 58, 398-415.e7. doi:10.1016/j.devcel.2023.02.006. https://pubmed.ncbi.nlm.nih.gov/36868233/

3. Rogier, Mélanie, Moritz, Jacques, Robert, Isabelle, Deriano, Ludovic, Reina-San-Martin, Bernardo. 2021. Fam72a enforces error-prone DNA repair during antibody diversification. In Nature, 600, 329-333. doi:10.1038/s41586-021-04093-y. https://pubmed.ncbi.nlm.nih.gov/34819671/

4. Barbulescu, Philip, Chana, Chetan K, Wong, Matthew K, Sicheri, Frank, Martin, Alberto. 2024. FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation. In Nature communications, 15, 7541. doi:10.1038/s41467-024-52009-x. https://pubmed.ncbi.nlm.nih.gov/39215025/

5. Zeng, Yibin, Xiong, Cui, Tang, Nan, Li, Menglong, Li, Junjun. 2023. FAM72A promotes glioma progression by regulating mitophagy through the Pink1/Parkin signaling pathway. In Journal of Cancer, 14, 903-915. doi:10.7150/jca.82949. https://pubmed.ncbi.nlm.nih.gov/37151394/

6. Zhou, Qi, Chen, Lingjun, Yang, Luo, Chen, Yan, Guo, Yunwei. 2022. Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma. In Frontiers in oncology, 12, 1046473. doi:10.3389/fonc.2022.1046473. https://pubmed.ncbi.nlm.nih.gov/36483027/

7. Gao, Wenyu, Ma, Yanping. . Expression and Function of FAM72A Gene in Multiple MyelomaFAM72A. In Current pharmaceutical biotechnology, 26, 455-464. doi:10.2174/0113892010311258240729080309. https://pubmed.ncbi.nlm.nih.gov/39129160/