Biology subjects

Crompton, A.

Publications and source records attributed to Crompton, A..

3 recordsLinked to original sources

bioRxiv2025

DNASE1L3 surveils mitochondrial DNA on the surface of distinct mammalian cells

The extracellular space is a critical environment for discriminating self versus non-self nucleic acids and initiating the appropriate immune responses through signaling cascades to relay information about extracellular nucleic acids. Here, we provide evidence that oxidized mitochondrial DNA is tethered to the surface of select mammalian cells through cell surface proteins and heparan sulfate proteoglycans. We demonstrate that cell surface DNA accumulates in large clusters that partially overlap with domains enriched in RNA binding proteins. Finally, we show that human and murine B cell surfaces contain DNA that can be cleared by the secreted nuclease DNASE1L3, and that patients with a DNASE1L3 missense variant associated with increased risk for autoimmune disease harbor increased levels of surface DNA on B and T cells. Taken together, this work expands the scope of cell surface nucleic acid biology and provides a mechanistic link between cell surface molecules and DNA targeting in autoimmune disease.

cell biology↗

bioRxiv2025

REV1 inhibition enhances trinucleotide repeat mutagenesis

Trinucleotide repeat (TNR) instability has been implicated in the pathogenesis of numerous neurodegenerative disorders. Because TNR instability causes mutagenesis of the underlying gene, we refer to the repeat instability phenomenon as TNR mutagenesis in this study. While germline expansions destabilize TNR to cause disease anticipation, somatic cell TNR instability drives earlier onset of symptoms and further disease progression. However, the drivers behind these repeat length changes remain unclear. Current models suggest that DNA replication slippage events and the action of genome instability pathways, such as DNA repair, cause TNR mutagenesis. Whether mutagenic polymerases from the translesion synthesis (TLS) pathway result in TNR instability is unclear. TLS polymerases are best at bypassing difficult-to-replicate DNA regions due to bulky lesions or gaps in DNA. While some effects of TLS polymerases on TNR instability have been explored in lower organisms, evidence in human cells is lacking. Using a quantitative GFP reporter with expanded CAG repeats, we show that inhibition of the TLS polymerase REV1 by its inhibitor, JH-RE-06, or siRNA knockdown increases TNR instability and the underlying mutability. These results suggest that REV1 protects Trinucleotide repeat length mutagenesis through potential continuous DNA synthesis when replicative polymerases stall ahead of repeat secondary structures. Collectively, we present evidence of the role of the TLS pathway in TNR instability, with potential implications for understanding mutability mechanisms, disease biology, and therapeutic targeting.

genetics↗

bioRxiv2024

Ornamental radiance as a defence against mimicry at the monogamy-polygyny interface.

Ornament evolves though sexual selection when both monogamy or polygyny are equally viable. In this special situation monogamous females will be be able to reject unwanted polygynous suitors only if monogamous males are able distinguish themselves with a sign of fidelity. Since the most sexually advantageous trait value for any male to possess is the one that matches the mean female preference, any signs so created will persist when either monogamy or polygyny subsequently becomes a dominant strategy. Species will therefore accumulate traces of each passage through the monogamous-polygynous boundary which, in birds, can lead, among other outcomes, to a collage of patches of coloured plumage. If a species lives at the interface long enough a polygynous bird might be able to copy the sign of fidelity. One defence against this aggressive mimicry will be to evolve to a sign that is costly or difficult to copy. This process is modelled mathematically showing that if variation of female preference is increased the male phenotype will alter in unpredictable ways that defy a mimic, at a cost of possibly being maladapted. This causes an ornamental radiance that matches ideas of beauty in the human world.

evolutionary biology↗