bims-micesi 2023-02-26 papers

Issue of 2023–02–26
four papers selected by
Valentina Piano, Uniklinik Köln

Biology (Basel). 2023 Jan 26. pii: 189. [Epub ahead of print]12(2):

HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells.

Aadil Javed, Gülseren Özduman, Lokman Varışlı, Bilge Esin Öztürk, Kemal Sami Korkmaz.

HN1 has previously been shown as overexpressed in various cancers. In Prostate cancer, it regulates AR signaling and centrosome-related functions. Previously, in two different studies, HN1 expression has been observed as inversely correlated with Cyclin B1. However, HN1 interacting partners and the role of HN1 interactions in cell cycle pathways have not been completely elucidated. Therefore, we used Prostate cancer cell lines again and utilized both transient and stable inducible overexpression systems to delineate the role of HN1 in the cell cycle. HN1 characterization was performed using treatments of kinase inhibitors, western blotting, flow cytometry, immunofluorescence, cellular fractionation, and immunoprecipitation approaches. Our findings suggest that HN1 overexpression before mitosis (post-G2), using both transient and stable expression systems, leads to S-phase accumulation and causes early mitotic exit after post-G2 overexpression. Mechanistically, HN1 interacted with Cyclin B1 and increased its degradation via ubiquitination through stabilized Cdh1, which is a co-factor of the APC/C complex. Stably HN1-expressing cells exhibited a reduced Cdt1 loading onto chromatin, demonstrating an exit from a G1 to S phenotype. We found HN1 and Cdh1 interaction as a new regulator of the Cyclin B1/CDK1 axis in mitotic regulation which can be explored further to dissect the roles of HN1 in the cell cycle.

Keywords: HN1; cell cycle; kinases; mitosis; prostate cancer; stable cell line

DOI: https://doi.org/10.3390/biology12020189

Genetics. 2023 Feb 22. pii: iyad028. [Epub ahead of print]

Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast.

Tra My Tran Nguyen, Arno Munhoven, Anke Samel-Pommerencke, Rucha Kshirsagar, Alessandro Cuomo, Tiziana Bonaldi, Ann E Ehrenhofer-Murray.

Posttranslational modifications on histones are well known to regulate chromatin structure and function, but much less information is available on modifications of the centromeric histone H3 variant and their effect at the kinetochore. Here, we report two modifications on the centromeric histone H3 variant CENP-A/Cse4 in the yeast Saccharomyces cerevisiae, methylation at arginine 143 (R143me) and lysine 131 (K131me), that affect centromere stability and kinetochore function. Both R143me and K131me lie in the core region of the centromeric nucleosome, near the entry/exit sites of the DNA from the nucleosome. Unexpectedly, mutation of Cse4-R143 (cse4-R143A) exacerbated the kinetochore defect of mutations in components of the NDC80 complex of the outer kinetochore (spc25-1) and the MIND complex (dsn1-7). The analysis of suppressor mutations of the spc25-1 cse4-R143A growth defect highlighted residues in Spc24, Ndc80 and Spc25 that localize to the tetramerization domain of the NDC80 complex and the Spc24-Spc25 stalk, suggesting that the mutations enhance interactions among NDC80 complex components and thus stabilize the complex. Furthermore, the Set2 histone methyltransferase inhibited kinetochore function in spc25-1 cse4-R143A cells, possibly by methylating Cse4-K131. Taken together, our data suggest that Cse4-R143 and -K131 methylation affect the stability of the centromeric nucleosome, which is detrimental in the context of defective NDC80 tetramerization and can be compensated for by strengthening interactions among NDC80 complex components.

Keywords: CENP-A; Cse4; Dsn1; Ndc80; Set2; Spc24; Spc25

DOI: https://doi.org/10.1093/genetics/iyad028

Ann Transl Med. 2023 Jan 31. 11(2): 117

Minghong Pan, Yuanyong Wang, Zhaoyang Wang, Hongtao Duan, Changjian Shao, Peng Ding, Jie Lei, Jinbo Zhao, Zhiqiang Ma, Fan Zhang, Jing Han, Xiaolong Yan.

Background: OIP5 is found at the centromere and plays an important role in recruiting centromere protein-A (CENP-A) through interacting with Holliday junction recognition protein during cell mitosis. OIP5 is considered to be a cancer-testis specific gene, but its function in tumor development remains unclear. Increased expression of OIP5 has been reported in testis as well as in different cancers; however, the underlying mechanisms remain obscure.
Methods: Data were collected from the Genotype-Tissue Expression project, the Cancer Cell Line Encyclopedia, and The Cancer Genome Atlas (TCGA) to analyze the effect of OIP5 in many common cancers. Analyses of the differential expression of OIP5 and its relationships with prognosis, the tumor microenvironment, immune infiltration, immune regulation, neoantigen production, and genomic stability in various cancers were performed using R software.
Results: Expression of OIP5 was significantly increased in 34 common tumor types compared with matched healthy samples; however, no significant increases were observed in pheochromocytoma and paraganglioma or kidney chromophobe. Elevated OIP5 expression predicted dismal overall survival in 14 tumors. The function of OIP5 in tumor-infiltrating immune cells (TIIC) was analyzed, and OIP5 might inhibit TIIC infiltration in the tumor microenvironment; a positive correlation was found in thymoma, while a negative correlation was observed in lung squamous cell carcinoma and lung adenocarcinoma. High OIP5 expression was related to immune regulation and neoantigen production, particularly in terms of the levels of immune regulatory molecules and the number of neoantigens produced in lung adenocarcinoma, uterine corpus endometrial carcinoma, breast cancer, stomach adenocarcinoma, low-grade glioma, and prostate adenocarcinoma. It was also associated with increased cell genome instability in lung adenocarcinoma. Gene set enrichment analysis revealed potential critical effects of OIP5 on the cell cycle, base excision repair, homologous recombination, DNA replication, the p53 signaling pathway, and mismatch repair pathways.
Conclusions: High expression of OIP5 is found in many common tumors and predicts a dismal prognostic outcome. The gene is an important recruitment factor for CENP-A and may promote tumor progression by affecting the tumor immune microenvironment and genomic stability. Therefore, OIP5 can serve as a potential candidate factor to predict cancer prognosis and guide the use of therapeutics.

Keywords: OIP5; mitosis; pan-cancer analysis

DOI: https://doi.org/10.21037/atm-22-6640

Antioxidants (Basel). 2023 Feb 20. pii: 531. [Epub ahead of print]12(2):

Aurora Kinase A Regulation by Cysteine Oxidative Modification.

In-Gyun Lee, Bong-Jin Lee.

Aurora kinase A (AURKA), which is a member of serine/threonine kinase family, plays a critical role in regulating mitosis. AURKA has drawn much attention as its dysregulation is critically associated with various cancers, leading to the development of AURKA inhibitors, a new class of anticancer drugs. As the spatiotemporal activity of AURKA critically depends on diverse intra- and inter-molecular factors, including its interaction with various protein cofactors and post-translational modifications, each of these pathways should be exploited for the development of a novel class of AURKA inhibitors other than ATP-competitive inhibitors. Several lines of evidence have recently shown that redox-active molecules can modify the cysteine residues located on the kinase domain of AURKA, thereby regulating its activity. In this review, we present the current understanding of how oxidative modifications of cysteine residues of AURKA, induced by redox-active molecules, structurally and functionally regulate AURKA and discuss their implications in the discovery of novel AURKA inhibitors.

Keywords: Aurora kinase A (AURKA); cysteine oxidative modification; redox-active molecules

DOI: https://doi.org/10.3390/antiox12020531