Biology subjects

West, K. L.

Publications and source records attributed to West, K. L..

3 recordsLinked to original sources

bioRxiv2024

Rare SNP in the HELB gene interferes with RPA interaction and cellular function of HELB

HELB is a human helicase involved in initiation of DNA replication, the replication stress response, and regulation of double-strand DNA break repair. rs75770066 is a rare SNP in the HELB gene that affects age at natural menopause. rs75770066 results in a D506G substitution in an acidic patch within the 1A domain of the helicase that is known to interact with RPA. We found that this amino acid change dramatically impairs the cellular function of HELB. D506G-HELB exhibits impaired interaction with RPA, which likely results in the effects of rs75770066 as this reduces recruitment of HELB to sites of DNA damage. Reduced recruitment of D506G-HELB to double-strand DNA breaks and the concomitant increase in homologous recombination likely alters the levels of meiotic recombination, which affects the viability of gametes. Because menopause occurs when oocyte levels drop below a minimum threshold, altered repair of meiotic double-stranded DNA breaks has the potential to directly affect the age at natural menopause.

biochemistry↗

bioRxiv2021

EZH2 inhibition in glioblastoma stem cells increases the expression of neuronal genes and the neuronal developmental regulators ZIC2, ZNF423 and MAFB

Glioblastoma multiforme (GBM) is an aggressive brain cancer with a very poor prognosis. It has been shown that GBM stem cells within a GBM tumour have increased resistance to standard therapies, so new approaches are needed to increase the range of treatment options available. Here we use two GBM stem cell lines, representing the classical/pro-neural and mesenchymal GBM subtypes, to investigate the effects of three different EZH2 inhibitors on GBM stem cell survival and gene expression: EPZ6438, GSK343 and UNC1999. EZH2 is the catalytic component of the PRC2 chromatin repressor complex, which represses transcription through methylation of histone H3 at lysine 27. Both cell lines showed significantly reduced colony formation after 48-hour exposure to the inhibitors, indicating they were sensitive to all three EZH2 inhibitors. RNA-seq analysis revealed that all three EZH2 inhibitors led to increased expression of genes related to neurogenesis and/or neuronal structure in both GBM stem cell lines. Chromatin immunoprecipitation (ChIP-Seq) was used to identify potential direct targets of the histone methylation activity of EZH2 that might be driving the increase in neuronal gene expression. Three genes were identified as candidate regulatory targets common to both cell lines: MAFB, ZIC2 and ZNF423. These transcription factors all have known roles in regulating neurogenesis, brain development and/or neuronal function. Through analysis of three different EZH2 inhibitors and two GBM stem cell lines, this study demonstrates a common underlying mechanism for how inhibition of EZH2 activity reduces GBM stem cell proliferation and survival.

cancer biology↗

bioRxiv2017

Multiple introductions of Zika virus into the United States revealed through genomic epidemiology

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital syndromes1,2. In July 2016, mosquito-borne ZIKV transmission was first reported in the continental United States and since then, hundreds of locally-acquired infections have been reported in Florida3. To gain insights into the timing, source, and likely route(s) of introduction of ZIKV into the continental United States, we tracked the virus from its first detection in Miami, Florida by direct sequencing of ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least four distinct ZIKV introductions contributed to the outbreak in Florida and that local transmission likely started in the spring of 2016 - several months before its initial detection. By analyzing surveillance and genetic data, we discovered that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions are phylogenetically linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. By comparing mosquito abundance and travel flows, we describe the areas of southern Florida that are especially vulnerable to ZIKV introductions. Our study provides a deeper understanding of how ZIKV initiates and sustains transmission in new regions.

epidemiology↗