Biology subjects

Morgan, R. G.

Publications and source records attributed to Morgan, R. G..

3 recordsLinked to original sources

bioRxiv2022

Detection of Borrelia garinii in the USA

Borrelia garinii, is a cause of Lyme disease in Europe and Asia. For the first time, we report it in the southeastern United States in rodents. Whole genome sequencing and phylogenetic analysis revealed that USA-located B. garinii is part of a clade consisting primarily of few European and majority of Far Eastern strains. Continued surveillance of wildlife hosts and ticks is necessary to assess the ecological status and public health risks of B. garinii in southeastern US.

microbiology↗

bioRxiv2021

Crosstalk between β-catenin and WT1 signalling activity in acute myeloid leukemia

Wnt signalling is an evolutionary conserved signal transduction pathway heavily implicated in normal development and disease. The central mediator of this pathway, {beta}-catenin, is frequently overexpressed, mislocalised and overactive in acute myeloid leukaemia (AML) where it mediates the establishment, maintenance and drug resistance of leukaemia stem cells. Critical to the stability, localisation and activity of {beta}-catenin are the protein-protein interactions it forms, yet these are poorly defined in AML. We recently performed the first {beta}-catenin interactome study in blood cells of any kind and identified a plethora of novel interacting partners. This study shows for the first time that {beta}-catenin interacts with Wilms tumour protein (WT1), a protein frequently overexpressed and mutated in AML, in both myeloid cell lines and also primary AML samples. We demonstrate crosstalk between the signalling activity of these two proteins in myeloid cells, and show that modulation of either protein can affect expression of the other. Finally, we demonstrate that WT1 mutations frequently observed in AML can increase stabilise {beta}-catenin and augment Wnt signalling output. This study has uncovered new context-dependent molecular interactions for {beta}-catenin which could inform future therapeutic strategies to target this dysregulated molecule in AML. Article summaryO_LI{beta}-Catenin is frequently dysregulated in acute myeloid leukemia (AML) and protein interactions govern its stability, localization and activity, but these are poorly defined in AML. C_LIO_LIThis study shows for the first time that {beta}-catenin and Wilms tumour protein (WT1) interact and influence each others expression level and signalling activity in AML cells, which could inform future therapeutic strategies. C_LI

cancer biology↗

bioRxiv2021

Loss of BCL-3 sensitises colorectal cancer cells to DNA damage, revealing a role for BCL-3 in double strand break repair by homologous recombination

ObjectiveThe proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC) and increased expression of the gene correlates with poor patient prognosis. The aim is to investigate whether inhibiting BCL-3 can increase the response to DNA damage in CRC. DesignThe function of BCL-3 in DNA damage response was studied in vitro using siRNA and CRISPR-Cas9 genome editing and in vivo using Bcl3-/- mice. DNA damage induced by {gamma}-irradiation and/or cisplatin was quantified using H2AX and RAD51 foci, repair pathways investigated using HR/NHEJ assays and treatment with the PARP inhibitor olaparib. ResultSuppression of BCL-3 increases double strand break number and decreases homologous recombination in CRC cells, supported by reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3-/- mice, where the intestinal crypts of these mice exhibit sensitivity to DNA damage and a greater number of double strand breaks compared to wild type mice. Furthermore Apc.Krasmutant x Bcl3-/- mice exhibit increased DNA damage and reduced RAD51+ cells compared to their wild type counterparts when treated with cisplatin. ConclusionThis work identifies BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjuvant to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.

cancer biology↗