Biology subjects

Islam, K. N.

Publications and source records attributed to Islam, K. N..

4 recordsLinked to original sources

bioRxiv2026

A SIRT5-induced metabolic switch underlies chemoresistance and ATR checkpoint dependence in triple-negative breast cancer

Chemoresistance is the leading cause of poor prognosis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain unknown. To reveal metabolic drivers of de novo chemoresistance in TNBC, we analyzed pretreatment primary tumor biopsies, employing quantitative proteomics and metabolomics. Chemoresistant TNBCs exhibit hallmarks of oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism linked to overexpression of the mitochondrial sirtuin, SIRT5. Through gain- and loss-of-function studies and stable isotope tracing, we demonstrate that SIRT5 induces a coordinated metabolic switch that redirects glycolysis to the pentose phosphate pathway, thereby augmenting nucleotide pools, while enhancing glutaminolysis to support OXPHOS. Mechanistically, SIRT5 enhances conversion of 6-phospho-D-gluconate to ribulose-5-phosphate through demalonylation of 6-phosphogluconate dehydrogenase (6-PGD), and coordinately activates oncogenic c-MYC to promote glutamine utilization and dependence. Concurrently, SIRT5-induced nucleotide deregulation induces replication stress and hypersensitivity to ATR checkpoint activation, and ATR inhibition synergistically reverses chemoresistance in TNBC. Thus, elevated SIRT5 orchestrates a coordinated metabolic switch to expand nucleotide pools and drive chemoresistance, while producing ATR checkpoint dependence that represents a metabolic vulnerability of SIRT5-overexpressing TNBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/716852v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1c7a27corg.highwire.dtl.DTLVardef@17cb22borg.highwire.dtl.DTLVardef@1956670org.highwire.dtl.DTLVardef@1786dee_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Enhancing Photosynthesis under Salt Stress via Directed Evolution in Cyanobacteria

A key aspect of enhancing photosynthesis is improving its recycling kinetics, enabling swift resumption of photochemical quenching following environmental disruptions or stress. Salt stress exacerbates high light stress in cyanobacteria and leads to severe yield losses in crop plants. Genetic traits that confer salt tolerance without compromising photosynthetic performance are essential for improving photosynthesis under these conditions. Here we applied accelerated evolution in Synechococcus elongatus PCC 7942 by conditionally suppressing its methyl-directed mismatch repair system to obtain beneficial genetic traits for enhanced photosynthesis under salt stress. Screening over 10,000 mutants, we isolated eight strains with increased biomass or sucrose productivity under salt stress. Genome sequencing revealed an average of 8-20 single nucleotide polymorphisms (SNPs) or indels per genome. Notably, mutations in the photosystem II (PSII) reaction center D1 gene, resulting in the amino acid changes L353F, I358N, and H359N at the carboxyl terminus of the pre-D1 (pD1) protein, improve photosynthesis under salt and combined salt and light stress by potentially accelerating D1 maturation during PSII repair. Phylogenetic analysis of pD1 across cyanobacteria and red algae highlights the broad significance of these adaptive genetic traits, underscoring the importance of leveraging evolutionary insights to improve photosynthesis under stress or fluctuating environments.

plant biology↗

bioRxiv2022

The RNA-binding protein Adad1 is necessary for germ cell maintenance and meiosis in zebrafish

The double stranded RNA binding protein Adad1 (adenosine deaminase domain containing 1) is a member of the adenosine deaminase acting on RNAs (Adar) protein family with germ cell-specific expression. In mice, Adad1 is necessary for sperm differentiation, however its function outside of mammals has not been investigated. Here, through an N-ethyl-N-nitrosourea (ENU) based forward genetic screen, we identified an adad1 mutant zebrafish line that develop as sterile males. Further histological examination revealed complete lack of germ cells in adult mutant fish, however germ cells populated the gonad, proliferated, and entered meiosis in larval and juvenile fish. Although meiosis was initiated in adad1 mutant testes, the spermatocytes failed to progress beyond the zygotene stage. Thus, Adad1 is essential for meiosis and germline maintenance in zebrafish. We tested if spermatogonial stem cells were affected using a label retaining cell (LRC) assay and found that the mutant testes had fewer LRCs compared to wild-type siblings, suggesting that failure to maintain the spermatogonial stem cells resulted in germ cell loss by adulthood. To identify potential molecular processes regulated by Adad1, we sequenced bulk mRNA from mutants and wild-type testes and found mis-regulation of genes involved in RNA stability and modification, pointing to a potential broader role in post-transcriptional regulation. Our findings suggest that Adad1 is an RNA regulatory protein required for fertility through regulation of spermatogonial stem cell maintenance in zebrafish. Author SummaryInfertility is a serious problem for millions of couples who wish to have children. Globally more than 10% of couples suffer from infertility due to genetic, epigenetic, and environmental factors. Among these about 50% of cases occur due to genetic factors such as aneuploidy and genetic mutations affecting development of the gametes (i.e. sperm and eggs). Although many genes are known to be involved in germ cell development, genetic causes of infertility are still largely unexplained. Therefore, it is imperative to investigate genes involved in reproductive processes. In this study, we report that the adad1 gene is essential for germ cell maintenance and fertility in zebrafish. Our analysis of zebrafish adad1 mutants demonstrates that it is required for maintenance of the germline stem cells and for completion of meiosis. This is in contrast to mouse Adad1, which functions later in gamete development to regulate differentiation of haploid sperm. Our work on zebrafish adad1 has uncovered previously unknown roles of adad1 function in germline stem cell maintenance.

developmental biology↗

bioRxiv2021

The zebrafish meiotic cohesion complex protein Smc1b is required for key events in meiotic prophase I

The eukaryotic structural maintenance of chromosomes (SMC) proteins are involved in key processes of chromosome structure and dynamics. SMC1{beta} was identified as a component of the meiotic cohesion complex in vertebrates, which aids in keeping sister chromatids together prior to segregation in meiosis II and is involved in association of homologous chromosomes in meiosis I. The role of SMC1{beta} in meiosis has primarily been studied in mice, where mutant male and female mice are infertile due to germ cell arrest at pachytene and metaphase II stages, respectively. Here, we investigate the function of zebrafish Smc1b to understand the role of this protein more broadly in vertebrates. We found that zebrafish smc1b is necessary for fertility and has important roles in meiosis, yet has no other apparent roles in development. Therefore, smc1b functions primarily in meiosis in both fish and mammals. In zebrafish, we showed that smc1b mutant spermatocytes initiated telomere clustering in leptotene, but failed to complete this process and progress into zygotene. Furthermore, mutant spermatocytes displayed a complete failure of homolog pairing and synapsis. Interestingly, meiotic DNA double strand breaks occurred in the absence of Smc1b despite failed pairing and synapsis. Overall, our findings point to an essential role of Smc1b in the leptotene to zygotene transition during zebrafish spermatogenesis. In addition, ovarian follicles failed to form in smc1b mutants, suggesting an essential role in female meiosis as well. Our results indicate that there are some key differences in Smc1b requirement in meiosis among vertebrates: while Smc1b is not required for homologue pairing and synapsis in mice, it is essential for these processes in zebrafish.

developmental biology↗