Biology subjects

Millar, R.

Publications and source records attributed to Millar, R..

3 recordsLinked to original sources

bioRxiv2025

Distinct ATRX functions cooperate with 9-1-1 and CST complexesto safeguard replication and telomere integrity

Mutations in the ATRX chromatin remodeller predispose to a developmental genetic disorder and cancer, but how it safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX deficient cells. ATRX:CST synthetic lethality manifests following accumulation of telomeric G-rich ssDNA, which results in telomere loss and cell death. Conversely, we attribute ATRX:9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable requiring its ATPase activity and PIP-box, respectively, and independently of its DAXX interaction. Collectively, functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.

molecular biology↗

bioRxiv2020

Introducing selfisher: open source software for statistical analyses of fishing gear selectivity

Fishing gear is constantly being improved to select certain sizes and species while excluding others. Experiments are conducted to quantify the selectivity and the resulting data needs to be analyzed using specialized statistical methods in many cases. Here, we present a new estimation tool for analyzing this type of data: an R package named selfisher. It can be used for both active and passive gears, and can handle different trial designs. It allows fitting models containing multiple fixed effects (e.g. length, total catch weight, mesh size, water turbidity) and random effects (e.g. haul). A bootstrapping procedure is provided to account for between and within haul variability and overdispersion. We demonstrate its use via four case studies including (1) covered codend analyses of four gears, (2) a paired gear study with numerous potential covariates, (3) a catch comparison study of unpaired hauls of gillnets and (4) a catch comparison study of paired hauls using polynomials and splines. This free and open source software will make it easier to model fishing gear selectivity, teach the statistical methods, and make analyses more repeatable.

ecology↗

bioRxiv2020

The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer

Triple negative breast cancer is the most aggressive subtype of breast cancer with poor prognosis and high rates of relapse. The lack of actionable targets for TNBC has contributed to the high mortality rates of this disease, and new candidate molecules for potential manipulation are urgently required. Here, we show that macrophage-stimulating protein (MSP) and its tyrosine kinase receptor, RON, are potent drivers of cancer cell growth and tumor progression in a mouse model of TNBC driven by the loss of Trp53 and Brca1. After comparison of two genetically engineered mouse models of TNBC, we found that mammary tumors from K14-Cre;Brca1F/F;Trp53F/F (KB1P) mice exhibit high endogenous levels of MSP and RON expression. We show that MSP stimulates AKT and ERK1/2 activation as well as cancer cell growth in KB1P cell lines, while genetic and pharmacological inhibition of RON prevents these effects. Similarly, KB1P tumor progression in mice was robustly attenuated by treatment with a RON inhibitor with accompanied reduction in the proliferation marker, Ki-67. Our findings in a mouse model where MSP and RON expression are naturally increased provide evidence that this receptor and its ligand are viable candidate molecules for targeted treatment of TNBC.

cancer biology↗