Biology subjects

Nguyen, M. M.

Publications and source records attributed to Nguyen, M. M..

4 recordsLinked to original sources

bioRxiv2024

Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells

The WRN RECQ helicase is responsible for the Werner syndrome of premature aging and cancer predisposition. Substantial progress has been made in delineating WRN functions in multiple aspects of DNA metabolism, including DNA replication, repair, transcription, and telomere maintenance. Nevertheless, a complete mechanistic understanding of how loss of WRN accelerates aging in humans has not been achieved yet. Here we show that WRN is involved in the maintenance of constitutive heterochromatin, CH, in proliferating, immortalized human fibroblasts. WRN is found within a complex with histone deacetylase 2, HDAC2, and WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1. WRN deficiency derepresses SATII pericentromeric satellite repeats and reduces a subset of protein-protein interactions that participate in the organization of CH in the nucleus. In particular, WRN deficiency reduces the complexes involving Lamin B1 and Lamin B receptor, LBR. Both mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and the latter phenotype does not require WRN catalytic activities. At the mRNA level, WRN supports complete maturation of the LBR mRNA. All signs of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence, and WRN complexes with HP1 and HDAC2 are also markedly downregulated in these senescing cells. The data suggest that WRN loss affects heterochromatin independently of the senescence program but can mimic aspects of it and thus sensitize cells to triggers of senescence.

molecular biology↗

bioRxiv2023

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

PurposeMetastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental designWe tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. ResultsWe demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. ConclusionThis work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

cancer biology↗

bioRxiv2023

Transcript errors generate a continuous stream of amyloid and prion-like proteins in human cells

Aging is characterized by the accumulation of amyloid and prion-like proteins. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that transcript errors generate amyloid and prion-like proteins in a wide variety of human cell types, including stem cells, brain organoids, and fully differentiated neurons. Intriguingly, some of these proteins are identical to proteins previously implicated in familial cases of amyloid diseases, raising the possibility that both familial and non-familial cases are caused by identical mutant proteins. However, transcript errors also generate amyloid proteins that have not been observed before, suggesting that aging cells are exposed to a second class of pathogenic proteins we are currently unaware of. Finally, we show that transcript errors are readily generated by DNA damage, a hallmark of human aging and a staple of multiple proteotoxic diseases, including Alzheimers disease. Together, these observations greatly expand our understanding of mutagenesis in human aging and disease and suggest a new mechanism by which amyloid diseases can develop.

molecular biology↗

bioRxiv2022

Multi-tissue landscape of somatic mtDNA mutations indicates tissue specific accumulation and removal in aging

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) during aging has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G[->]A/C[->]T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G[->]T/C[->]A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age indicates a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.

genomics↗