Fam72a, a poorly characterized yet evolutionarily conserved gene across multicellular organisms, plays multifaceted roles [2]. It is a cell-cycle-regulated gene, transcriptionally regulated by FoxM1 and post-transcriptionally by APC/C. Functionally, it binds to tubulin and subunits of PP2A-B56, modulating tubulin and Mcl1 phosphorylation, thus influencing cell-cycle progression, apoptosis signaling, and chemotherapy responses [2]. In the context of antibody maturation, Fam72a is a key determinant for the error-prone processing of deoxyuracils [1,3].

Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/-mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, along with reduced genome-wide deoxyuracils [1]. The somatic hypermutation spectrum in B cells from Fam72a-/-mice is opposite to that in UNG2-deficient mice, suggesting hyperactive UNG2 in FAM72A-deficient cells [1]. FAM72A binds to UNG2, reducing UNG2 protein levels in the G1 phase, causing U·G mispairs to persist into S phase and leading to error-prone processing by mismatch repair [1]. Also, in multiple myeloma, overexpression of FAM72A in U266 cells promotes cell proliferation, inhibits apoptosis, and reduces sensitivity to bortezomib by regulating the POU2F2/FAM72A/p53 signaling pathway [4].

In summary, Fam72a is crucial for cell-cycle regulation, apoptosis, and antibody maturation. The study of Fam72a-deficient mouse models has revealed its role in antibody-related mutagenic repair and its potential significance in cancer-related processes such as in multiple myeloma, highlighting its importance as a potential therapeutic target in these disease areas [1,2,4].

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. 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/