Wdr26, or WD repeat-containing protein 26, is a core component of the carboxy-terminal to LisH (CTLH) E3 ubiquitin ligase complex. It plays diverse roles in multiple biological pathways. It is involved in non-canonical substrate recognition, regulating prodrug metabolism through binding to metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) [1]. It is also associated with pathways like the canonical Wnt signaling pathway where it acts as a negative regulator [5].

Genetic forward screening in a mouse model of multiple myeloma identified Wdr26 as a novel myeloma gene, suggesting it could be a therapeutic target [2]. In zebrafish and mouse models, loss of Wdr26 led to anemia in zebrafish and enucleation defects in mouse erythroblasts due to impaired nuclear condensation, revealing its role in terminal erythropoiesis [3]. In HeLa cells, knockout of Wdr26 affected chromatin accessibility and gene expression, implicating it in chromatin regulation [4].

In conclusion, Wdr26 is crucial for multiple biological processes, including metabolism, hematopoiesis, and chromatin regulation. Its study in genetic models like KO mouse models has revealed its potential as a therapeutic target in multiple myeloma. These models have provided insights into its roles in various disease-related processes, enhancing our understanding of disease mechanisms and potential treatment strategies.

References:

1. Gottemukkala, Karthik V, Chrustowicz, Jakub, Sherpa, Dawafuti, Schulman, Brenda A, Alpi, Arno F. . Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism. In Molecular cell, 84, 1948-1963.e11. doi:10.1016/j.molcel.2024.04.014. https://pubmed.ncbi.nlm.nih.gov/38759627/

2. Sun, Fumou, Cheng, Yan, Riordan, Jesse D, Hari, Parameswaran, Janz, Siegfried. 2021. WDR26 and MTF2 are therapeutic targets in multiple myeloma. In Journal of hematology & oncology, 14, 203. doi:10.1186/s13045-021-01217-9. https://pubmed.ncbi.nlm.nih.gov/34876184/

3. Zhen, Ru, Moo, Chingyee, Zhao, Zhenzhen, Shi, Jiahai, Chen, Caiyong. . Wdr26 regulates nuclear condensation in developing erythroblasts. In Blood, 135, 208-219. doi:10.1182/blood.2019002165. https://pubmed.ncbi.nlm.nih.gov/31945154/

4. Onea, Gabriel, Ghahramani, Alireza, Wang, Xu, Bérubé, Nathalie G, Schild-Poulter, Caroline. 2025. WDR26 depletion alters chromatin accessibility and gene expression profiles in mammalian cells. In Genomics, 117, 111001. doi:10.1016/j.ygeno.2025.111001. https://pubmed.ncbi.nlm.nih.gov/39837355/

5. Goto, Toshiyasu, Matsuzawa, Junhei, Iemura, Shun-Ichiro, Natsume, Tohru, Shibuya, Hiroshi. 2016. WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway. In FEBS letters, 590, 1291-303. doi:10.1002/1873-3468.12180. https://pubmed.ncbi.nlm.nih.gov/27098453/