Overexpression of the regulator gene hgc1 increases both the productivity and diversity of hygrocins, revealing the unprecedented flexibility in ansamycin biosynthesis.

Chemotherapy resistance represents a major issue associated with gastric cancer (GC) treatment, and arises through multiple mechanisms, including modulation of the cell-cycle check point. Several ubiquitin kinases, including RING finger protein 138 (RNF138), have been reported to mediate the G2/M phase arrest. In this study, we investigated the role of RNF138 in the development of cisplatin resistance of two GC cell lines. We show that RNF138 levels are higher in cisplatin-resistant cell lines, compared with cisplatin-sensitive cells, and RNF138 expression was elevated during drug withdrawal following the cisplatin treatment. Using gene overexpression and silencing, we analyzed the impact of altering RNF138 level on GC cell viability, apoptosis, and cell cycle phenotypes in two isogenic cisplatin-sensitive and resistant cell lines. We show that RNF138 overexpression increased GC cell viability, decreased apoptosis and delayed cell cycle progression in the cisplatin-sensitive GC cells. Conversely, RNF138 silencing produced opposite phenotypes in the cisplatin-resistant cells. Moreover, RNF138-dependent phosphorylation of Chk1 was seen in GC cells, indicating a novel connection between cisplatin-induced DNA damage and apoptosis. Collectively, these data suggest that RNF138 modulates the cisplatin resistance in the GC cells, thus serving as a potential drug target to challenge chemotherapy failure. In addition, RNF138 can also be used as a marker to monitor the development of cisplatin resistance in GC treatment. ARTICLE HISTORY

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In adult mammals, spermatogenesis embodies the complex transition from spermatogonial stem cells (SSCs) to spermatozoa. This process is initiated by the dynamic transition among a series of SSCs subpopulations. However, it remains elusive and controversial for the identity of the primitive adult SSCs at the top of this developmental hierarchy. Using single-cell analysis and lineage tracing, we identified forkhead box protein C2 (FOXC2) as a specific marker for the primitive SSCs subpopulation in adult mice and humans. During homeostasis, FOXC2+-SSCs can initiate spermatogenesis, and through which give rise to all sets of spermatogenic progenies. Specific ablation of the FOXC2+-SSC results in depletion of the undifferentiated spermatogonia pool. During germline regeneration, spermatogenesis can be completely restored by FOXC2+-SSCs. Germ cell specific Foxc2 knockout resulted in accelerated exhaustion of SSCs and eventually led to male infertility. Mechanistically, FOXC2 is required for maintaining the quiescent state of the primitive SSCs by promoting the expression of negative regulators of cell cycle phase transition. Overall, this work proposed FOXC2+-SSCs as an indispensable and primitive subgroup during homeostasis and regeneration in the adult testis.