Ddx39a, an ATP-dependent RNA helicase, is crucial for energy-driven RNA processing reactions. It is involved in pathways such as RNA splicing, nuclear export of RNA, and innate immunity regulation [3,4,7]. Its biological importance spans from normal cellular functions to responses against viral infections and in cancer-related processes [1,2,4,6,8,9]. Genetic models like KO/CKO mouse models could potentially be valuable in further elucidating its functions.

Genetic screening identified Ddx39a as antiviral against alphaviruses like chikungunya virus (CHIKV). It accumulates in the cytoplasm upon infection, inhibiting alphavirus replication independently of the canonical interferon pathway by binding to the 5' conserved sequence element of CHIKV genomic RNA [1]. In hepatocellular carcinoma, SNRPD2 drives Ddx39a intron retention, modulating the expression of a short variant (39A_S) that mediates MYC mRNA nuclear export, forming a positive-feedback loop [2]. Ddx39a and its highly homologous paralog Ddx39b have some redundant and some specific functions in alternative RNA splicing [3]. In HEK293T cells, Ddx39a traps mRNAs of antiviral signaling components in the nucleus, promoting virus proliferation, and its SUMOylation status affects this ability [4]. In human cells, Ddx39a resolves replication fork-associated RNA-DNA hybrids in transcriptionally active regions, balancing fork protection and cleavage for genomic stability [5]. Also, Ddx39a is highly expressed in undifferentiated neuroblastoma cells and primary tumor tissues of patients with poor prognosis, being a potential biomarker [6]. It interacts with ECD to regulate nuclear mRNA export, and its knockdown in ErbB2+ breast cancer cells affects ErbB2 mRNA levels and oncogenic traits [7]. In tongue squamous cell carcinoma, TRAIP may interact with Ddx39a to promote tumor progression through epithelial-mesenchymal transition and Wnt/β-catenin pathways [8]. Ddx39a acts as a negative regulator, impeding IFN production upon viral infection [9].

In conclusion, Ddx39a is multifunctional, playing key roles in antiviral defense, RNA processing, and cancer-related processes. Findings from various functional studies, though not specifically from KO/CKO mouse models in the provided references, have revealed its importance in controlling viral infections, regulating gene expression in cancer cells, and maintaining genomic stability. Understanding Ddx39a could potentially lead to new strategies for treating viral diseases and cancers.

References:

1. Tapescu, Iulia, Taschuk, Frances, Pokharel, Swechha M, Schultz, David C, Cherry, Sara. 2023. The RNA helicase DDX39A binds a conserved structure in chikungunya virus RNA to control infection. In Molecular cell, 83, 4174-4189.e7. doi:10.1016/j.molcel.2023.10.008. https://pubmed.ncbi.nlm.nih.gov/37949067/

2. Chang, Cunjie, Li, Lina, Su, Ling, Chabot, Benoit, Chen, Jianxiang. 2024. Intron Retention of DDX39A Driven by SNRPD2 is a Crucial Splicing Axis for Oncogenic MYC/Spliceosome Program in Hepatocellular Carcinoma. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403387. doi:10.1002/advs.202403387. https://pubmed.ncbi.nlm.nih.gov/39018261/

3. Banerjee, Shefali, Nagasawa, Chloe K, Widen, Steven G, Garcia-Blanco, Mariano A. . Parsing the roles of DExD-box proteins DDX39A and DDX39B in alternative RNA splicing. In Nucleic acids research, 52, 8534-8551. doi:10.1093/nar/gkae431. https://pubmed.ncbi.nlm.nih.gov/38801080/

4. Shi, Peidian, Guo, Yanyu, Su, Yanxin, Wu, Jiaqi, Huang, Jinhai. 2020. SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity. In Journal of immunology (Baltimore, Md. : 1950), 205, 168-180. doi:10.4049/jimmunol.2000053. https://pubmed.ncbi.nlm.nih.gov/32393512/

5. Xu, Zhanzhan, Nie, Chen, Liao, Junwei, Wang, Weibin, Wang, Jiadong. 2024. DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance. In Molecular cell, 85, 490-505.e11. doi:10.1016/j.molcel.2024.11.029. https://pubmed.ncbi.nlm.nih.gov/39706185/

6. Otake, Kohei, Uchida, Keiichi, Ide, Shozo, Kobayashi, Issei, Kusunoki, Masato. 2015. Identification of DDX39A as a Potential Biomarker for Unfavorable Neuroblastoma Using a Proteomic Approach. In Pediatric blood & cancer, 63, 221-7. doi:10.1002/pbc.25778. https://pubmed.ncbi.nlm.nih.gov/26469522/

7. Saleem, Irfana, Mirza, Sameer, Sarkar, Aniruddha, Band, Hamid, Band, Vimla. 2021. The Mammalian Ecdysoneless Protein Interacts with RNA Helicase DDX39A To Regulate Nuclear mRNA Export. In Molecular and cellular biology, 41, e0010321. doi:10.1128/MCB.00103-21. https://pubmed.ncbi.nlm.nih.gov/33941617/

8. Liu, Litong, Wang, Ping, Guo, Cheng, Xing, Xiaoming, Wang, Chengqin. 2024. TRAIP enhances progression of tongue squamous cell carcinoma through EMT and Wnt/β-catenin signaling by interacting with DDX39A. In BMC cancer, 24, 1481. doi:10.1186/s12885-024-13130-8. https://pubmed.ncbi.nlm.nih.gov/39623306/

9. Bonaventure, Boris, Goujon, Caroline. . DExH/D-box helicases at the frontline of intrinsic and innate immunity against viral infections. In The Journal of general virology, 103, . doi:10.1099/jgv.0.001766. https://pubmed.ncbi.nlm.nih.gov/36006669/