Upf3a, also known as up-frameshift 3A, is a key factor in the nonsense-mediated mRNA decay (NMD) pathway, which is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD is crucial for mRNA quality and quantity control, safeguarding multiple biological processes [2].

In mouse models, a conditional knockout (CKO) of Upf3a showed that it is dispensable for NMD when Upf3B is present in mouse embryonic stem cells, somatic cells, and major organs like the liver, spleen, and thymus. However, it may weakly and selectively promote NMD in certain murine organs [2]. In human cells, overexpression or knockout of Upf3a alone did not substantially change global NMD activity, but co-depletion of Upf3a and Upf3B led to marked NMD inhibition, demonstrating functional redundancy between the two [1]. In human colorectal cancer HCT116 cells, Upf3a is almost dispensable for NMD in wild-type cells but strongly activates NMD in cells lacking Upf3B [3].

In summary, Upf3a is involved in the NMD pathway, and its role in NMD shows redundancy with Upf3B. Mouse knockout models have revealed that Upf3a is generally dispensable for NMD in most cells and organs when Upf3B is present, but may have a weak promoting effect in some specific murine organs. In the context of cancer, such as colorectal cancer, Upf3a may play a role in tumor progression, with high expression associated with poor prognosis [4].

References:

1. Wallmeroth, Damaris, Lackmann, Jan-Wilm, Kueckelmann, Sabrina, Boehm, Volker, Gehring, Niels H. 2022. Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. In The EMBO journal, 41, e109191. doi:10.15252/embj.2021109191. https://pubmed.ncbi.nlm.nih.gov/35451084/

2. Chen, Chengyan, Shen, Yanmin, Li, Luqian, Wang, Zhao-Qi, Li, Tangliang. 2023. UPF3A is dispensable for nonsense-mediated mRNA decay in mouse pluripotent and somatic cells. In Life science alliance, 6, . doi:10.26508/lsa.202201589. https://pubmed.ncbi.nlm.nih.gov/36997282/

3. Yi, Zhongxia, Arvola, René M, Myers, Sean, Bundschuh, Ralf, Singh, Guramrit. 2022. Mammalian UPF3A and UPF3B can activate nonsense-mediated mRNA decay independently of their exon junction complex binding. In The EMBO journal, 41, e109202. doi:10.15252/embj.2021109202. https://pubmed.ncbi.nlm.nih.gov/35451102/

4. Bao, Xinmin, Huang, Yuji, Xu, Weimin, Xiong, Gongyou. 2020. Functions and Clinical Significance of UPF3a Expression in Human Colorectal Cancer. In Cancer management and research, 12, 4271-4281. doi:10.2147/CMAR.S244486. https://pubmed.ncbi.nlm.nih.gov/32606924/