Biology subjects

Flores, N.

Publications and source records attributed to Flores, N..

3 recordsLinked to original sources

bioRxiv2026

KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage

Chemoresistance remains a major obstacle to effective cancer treatment, often driven by enhanced DNA repair mechanisms that enable tumor cells to withstand genotoxic therapies. One such pathway involves the atypical DNA damage repair complex ALKBH3-ASCC, activated by the E3 ligase RNF113A in response to alkylation damage. We previously showed that SMYD3-dependent methylation of RNF113A stimulates this pathway, enhancing DNA repair and promoting resistance. Here, we identify KDM7B/PHF8 as the bona fide RNF113A demethylase, establishing one of the first functional examples of a dynamic, reversible non-histone methylation event regulating genome integrity. KDM7B antagonizes SMYD3 activity by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. To dissect this regulation in depth, we focused on small cell lung cancer (SCLC), a particularly aggressive malignancy characterized by limited therapeutic options and rapid acquisition of resistance. In SCLC, high KDM7B levels correlate with improved patient prognosis, whereas xenografts with reduced expression exhibit diminished responses to alkylating treatment. Moreover, CRISPR-based on/off modulation of KDM7B in genetically engineered SCLC mouse models demonstrates its central role in determining tumor response to chemotherapy. Our findings position the RNF113A-ASCC axis as a central modulator of chemoresistance, regulated through a post-translational methylation switch representing an innovative therapeutic vulnerability that could be exploited to enhance the efficacy of alkylating agents. Targeting this pathway may provide new opportunities to overcome chemoresistance, with KDM7B levels serving as a predictive biomarker to guide treatment in SCLC.

cell biology↗

bioRxiv2024

Sigma factors as potential targets to enhance recombinant protein expression

The transcriptional factors control the expression of many genes and represent an important layer of complexity in cell factories. However, the effect of individual sigma factor deletions from a biomanufacturing perspective has not been addressed. In this contribution, growth and oxygen consumption of E. coli BW25113 strains with individual inactivation of each sigma factor were characterized under various conditions. The deletion of rpoD has been reported to be lethal for E. coli. However, the evaluated rpoD mutant did not exhibit major growth defects in the mineral medium and is explained because the rpoD gene is duplicated in this strain. Recombinant protein was expressed at three different induction levels in a mineral and LB media. The fliA mutant was the best producer in the mineral medium, whereas the rpoD mutant overperformed the other strains in LB medium. This suggest that a lower rpoD gene dosage is positive for the performance of the cell factory in complex medium. In cultures at 20 {degrees}C, the rpoS mutant exhibited the greatest recombinant expression. To our knowledge, this is the first systematic study evaluating the potential of sigma factor deletion for improving recombinant protein production.

microbiology↗

bioRxiv2022

Exploring Viral Communities Associated With Terrestrial Cyanobacteria Metagenomes

Viruses are exceedingly common, but little is known about their diversity let alone how they behave in extreme environments, and whether viruses facilitate adaptation of their hosts to harsh conditions. To set a foundation for understanding of these understudied viral-host interactions, we created a catalog of viruses through analysis of metagenomes from 50 unialgal but nonaxenic Cyanobacteria cultures with 47 cultures isolated from various terrestrial habitats, including desert soil and rock surfaces, tropical soil, and vernal pools. These cultures represent low diversity microbial consortia dominated by the terrestrial Cyanobacteria and its associated cyanosphere microbiome containing heterotrophic microbes. We identified viral sequences in metagenomes, grouped these into viral operational taxonomic units (vOTUs) and then placed vOTUs into viral clusters (VCs). We also calculated vOTU relative abundance and predicted possible bacterial hosts. In total we predicted 814 viral sequences representing 726 vOTUs. We assigned putative taxonomy to 72 of the 814 putative viral sequences; these were distributed into 15 VCs -- mostly assigned to the recently abolished Caudovirales order (now Caudoviricetes class) of viruses. We found that nonaxenic cultures were dominated by unclassified and unclustered viral sequences. Furthermore, we predicted putative bacterial hosts for 211 vOTUs, with the majority of viruses predicted to infect a Proteobacteria (now Pseudomonadota) host. Overall, while limited, these results are consistent with the notion that both viruses and Cyanobacteria isolated from extreme environments are underrepresented in reference datasets. This work increases knowledge of viral diversity and sets a foundation for future exploration of viruses associated with terrestrial Cyanobacteria and their heterotroph associates, such as connecting specific viruses to critical cycling processes and investigating their metabolic functions.

microbiology↗