Nme5, a member of the NME/NM23 family of nucleoside diphosphate kinases (NDPK), is associated with ciliary function [1,3,6]. It is also involved in DNA-related functions as some NME proteins, including Nme5, exhibit 3'-5' exonuclease activity, suggesting roles in DNA proofreading and repair [5]. Group II NME proteins like Nme5, which contain a single or several different NDK domains sometimes associated with extra-domains, do not typically display measurable NDPK activity [2].

In Alaskan Malamutes, a frameshift variant (c.43delA) in Nme5 causes primary ciliary dyskinesia (PCD), with affected Nme5 -/- knockout mice showing doming of the skull, hydrocephalus, and sperm flagellar defects [1]. In humans, a homozygous nonsense variant (c.572G>A; p.Trp191*) in Nme5 was identified in a PCD patient with situs solitus, and morpholino knockdown of nme5 in zebrafish embryos led to motile cilia defects [3]. Additionally, Nme5 has been linked to gemcitabine resistance in pancreatic cancer cells, where its down-regulation reversed resistance, and over-expression induced resistance, likely through attenuating apoptosis and cell cycle arrest in a NF-κB-dependent manner [4].

In summary, Nme5 is crucial for ciliary function as demonstrated by animal models with Nme5 loss-of-function leading to PCD-related phenotypes. It also plays a role in pancreatic cancer drug resistance. Understanding Nme5 function through gene-knockout models provides insights into the mechanisms of PCD and potential treatment strategies for pancreatic cancer.

References:

1. Anderegg, Linda, Im Hof Gut, Michelle, Hetzel, Udo, Jagannathan, Vidhya, Leeb, Tosso. 2019. NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia. In PLoS genetics, 15, e1008378. doi:10.1371/journal.pgen.1008378. https://pubmed.ncbi.nlm.nih.gov/31479451/

2. Perina, Dragutin, Korolija, Marina, Mikoč, Andreja, Herak Bosnar, Maja, Ćetković, Helena. 2019. Characterization of Nme5-Like Gene/Protein from the Red Alga Chondrus Crispus. In Marine drugs, 18, . doi:10.3390/md18010013. https://pubmed.ncbi.nlm.nih.gov/31877804/

3. Cho, Eun Hye, Huh, Hee Jae, Jeong, Inyoung, Park, Hae-Chul, Ki, Chang-Seok. 2020. A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects. In Clinical genetics, 98, 64-68. doi:10.1111/cge.13742. https://pubmed.ncbi.nlm.nih.gov/32185794/

4. Li, Fu, Hu, Gang, Jiang, Zhenzhou, Qin, Xiaoran, Zhang, Luyong. 2012. Identification of NME5 as a contributor to innate resistance to gemcitabine in pancreatic cancer cells. In The FEBS journal, 279, 1261-73. doi:10.1111/j.1742-4658.2012.08521.x. https://pubmed.ncbi.nlm.nih.gov/22325559/

5. Puts, Gemma S, Leonard, M Kathryn, Pamidimukkala, Nidhi V, Snyder, Devin E, Kaetzel, David M. 2017. Nuclear functions of NME proteins. In Laboratory investigation; a journal of technical methods and pathology, 98, 211-218. doi:10.1038/labinvest.2017.109. https://pubmed.ncbi.nlm.nih.gov/29058704/

6. Sahabian, Anais, von Schlehdorn, Laura, Drick, Nora, Ringshausen, Felix C, Olmer, Ruth. 2020. Generation of two hiPSC clones (MHHi019-A, MHHi019-B) from a primary ciliary dyskinesia patient carrying a homozygous deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)). In Stem cell research, 48, 101988. doi:10.1016/j.scr.2020.101988. https://pubmed.ncbi.nlm.nih.gov/32950024/