Biology subjects

O'Sullivan, R. J.

Publications and source records attributed to O'Sullivan, R. J..

7 recordsLinked to original sources

bioRxiv2025

SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres

The tRNA nuclease SLFN11 is epigenetically silenced in [~]50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To acquire immortality, cancer cells can activate alternative lengthening of telomeres (ALT), typically accompanied by ATRX loss. Here, we implicate SLFN11 in sensing telomere replication stress, triggering eradication of ATRX deficient cells prior to ALT establishment. Whereas progressive telomere shortening of cells lacking telomerase and ATRX leads to telomere crisis and cell death, SLFN11 loss confers tolerance to PML-BLM dependent ALT intermediates, permitting emergence of ALT survivors. We propose that during tumorigenesis SLFN11 inactivation is selected as means to tolerate endogenous replication stress following telomere crisis, leading to the development of therapy resistant tumours before treatment.

molecular biology↗

bioRxiv2024

Food quality and vgll3 genotype influence reproductive traits in female Atlantic salmon

Age at maturity is an important factor contributing to life-history diversity. In Atlantic salmon, this trait often shows sex-specific variation, but female salmon are seldom included in experimental studies of maturation. As a result, there is a gap in our knowledge of how different genetic and environmental factors affect female maturation. Using a 4-year common-garden experiment, we assessed the influence of diet (low-fat vs. control) and vgll3 (a candidate gene in a genomic region known to influence age at maturity in Atlantic salmon) on maturation and related phenotypic traits of female Atlantic salmon from two 2nd-generation hatchery populations. We found the early-maturation-associated vgll3*E allele to be associated with higher probability of maturation. Heritability of maturation was estimated to be 0.295 with vgll3s contribution to phenotypic variance being [~]2%. In addition, both body size and body condition measured in the spring prior to spawning influenced maturation. Body condition, in turn, was influenced by population and diet. The northern Oulu population and the low-fat diet were associated with lower body condition compared to the southern Neva population and the control diet. Moreover, there was an interaction between population and diet on body condition, suggesting that populations may respond differently to nutrient availability. These results broaden our understanding of the processes underlying maturation and demonstrate that genes and environment interact to shape age at maturity in female Atlantic salmon.

evolutionary biology↗

bioRxiv2024

TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling

An inability to replicate the genome can cause replication stress and genome instability. Here, we develop BLOCK-ID, a proteomic method to identify and visualize proteins at stressed replication forks. This approach successfully identified novel mediators of the replication stress response, including the chromatin acetylation reader protein TRIM24. In validating TRIM24 function, we uncovered its crucial role in coordinating Alternative Lengthening of Telomeres (ALT), a cancer-specific telomere extension pathway involving replication stress. Our data reveal that TRIM24 is directed to telomeres via a p300/CBP-dependent acetylation chromatin signaling cascade, where it organizes ALT-associated PML bodies (APBs) to promote telomere DNA synthesis. Strikingly, we demonstrate that when artificially tethered at telomeres, TRIM24 can stimulate new telomere DNA synthesis in a SUMO-dependent manner, independently of p300/CBP or PML-dependent APBs. Thus, this study identifies a TRIM24 chromatin signaling pathway required for ALT telomere maintenance.

cell biology↗

bioRxiv2024

SUMO Promotes DNA Repair Protein Collaboration to Support Alterative Telomere Lengthening in the Absence of PML

Alternative lengthening of telomeres (ALT) pathway maintains telomeres in a significant fraction of cancers associated with poor clinical outcomes. A better understanding of ALT mechanisms can provide a basis for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins plays a critical role in the formation of ALT telomere-associated PML bodies (APBs), where telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, whether and how SUMO contributes to ALT beyond APB formation remains elusive. Here, we report that SUMO promotes collaboration among DNA repair proteins to achieve APB-independent telomere maintenance. By using ALT cancer cells with PML protein knocked out and thus devoid of APBs, we show that sumoylation is required for manifesting ALT features, including telomere clustering and telomeric DNA synthesis, independent of PML and APBs. Further, small molecule-induced telomere targeting of SUMO produces signatures of phase separation and ALT features in PML null cells in a manner depending on both sumoylation and SUMO interaction with SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are linked to the enrichment of DNA repair proteins, including Rad52, Rad51AP1, and BLM, to the SUMO-containing telomere foci. Finally, we find that Rad52 can undergo phase separation, enrich SUMO on telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that, in addition to forming APBs, SUMO also promotes collaboration among DNA repair proteins to support telomere maintenance in ALT cells. Given the promising effects of sumoylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.

cell biology↗

bioRxiv2023

Soft selection affects introgression dynamics and the viability of populations experiencing intrusion of maladapted individuals

The deliberate release of captive-bred individuals, the accidental escape of domesticated strains, or the invasion of closely related conspecifics into wild populations can all lead to introgressive hybridisation, which poses a challenge for conservation and wildlife management. Rates of introgression and the magnitude of associated demographic impacts vary widely across ecological contexts. However, the reasons for this variation remain poorly understood. One rarely considered phenomenon in this context is soft selection, wherein relative trait values determine success in intraspecific competition for a limiting resource. Here we develop an eco-genetic model explicitly focussed on understanding the influence soft selection has on the eco-evolutionary dynamics of wild populations experiencing intrusion from foreign/domesticated individuals. While based on a generalised salmonine lifecycle, the model is applicable to any taxon that experiences incursion from locally maladapted genotypes, in addition to phenotype-dependent competition for a limiting resource (e.g., breeding sites, feeding territories). The effects of both acute and chronic intrusion depended strongly on the relative competitiveness of intruders versus locals. When intruders were competitively inferior, soft selection limited their reproductive success (ability to compete for limited spawning sites), which prevented strong introgression or population declines from occurring. In contrast, when intruders were competitively superior, this amplified introgression and led to increased maladaptation of the admixed population. This had negative consequences for population size and population viability. The results were sensitive to the intrusion level, the magnitude of reproductive excess, trait heritability, and the extent to which intruders were maladapted relative to locals. Our findings draw attention to under- appreciated interactions between soft selection and maladaptive hybridisation, which may be critical to determining the impact captive breeding programmes and domesticated escapees can have on otherwise self-sustaining wild populations.

evolutionary biology↗

bioRxiv2023

Extrachromosomal Telomeres Derived from Excessive Strand Displacements

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication (BIR), evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), unique to ALT cells, are considered potential precursors of C-circles, their generation process remains undefined. Here, we introduce a highly sensitive method to detect single stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single stranded DNAs that are near 200 to 1500 nucleotides in size. Both linear C-rich ssDNAs and C-circles are abundant in the fractions of cytoplasm and nucleoplasm, which supports the idea that linear C-rich ssDNA accumulation may indeed precede C-circle formation. We also found that C-rich ssDNAs originate during Okazaki fragment processing during lagging strand DNA synthesis. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha) complex-mediated priming of the C-strand DNA synthesis and subsequent excessive strand displacement of the C-rich strand mediated by the DNA Polymerase delta and the BLM helicase. Our work proposes a new model for the generation of C-rich ssDNAs and C-circles during ALT-mediated telomere elongation.

biochemistry↗

bioRxiv2022

Genetic stock identification reveals greater use of an oceanic feeding ground around the Faroe Islands by multi-sea winter Atlantic salmon.

There is a general paucity of knowledge regards spatial variation in marine resource use for many taxa, even those of high socio-economic importance such as Atlantic salmon. While it is known that the oceans around the Faroe Islands support a salmon feeding ground, the relative use of this feeding ground by different age classes across different stocks remains largely unexplored. Using a combination of genetic stock assignment and run-reconstruction models, we observed a consistent pattern whereby the proportion of multi-sea winter (MSW) salmon for a given reporting group was substantially greater around the Faroes than the MSW proportion for that reporting groups among the prefisheries abundance. Surprisingly, MSW fish from Ireland and UK were as likely to occur around the Faroes as were MSW fish from more north-eastern regions such as the Teno river and the Barents and White Seas. MSW fish from Southern Norway were the most likely to be caught at the Faroes. While 1SW salmon from Ireland and UK as well as from Southern Norway occurred at similar rates around the Faroes, 1SW fish from more north-eastern reporting groups were nearly entirely absent from the same feeding ground. In combination with previous studies that examine the marine distribution of Atlantic salmon, our results strongly indicate that the oceans around the Faroes play host to a predominantly MSW salmon feeding ground and that use of this resource varies both within the age classes of a given stock as well as between different stocks. Furthermore, these results suggest that MSW fish from certain stocks might preferentially undertake migrations to the Faroes. Variation in spatial resource use may help to buffer salmon stocks against localised negative changes in marine conditions.

ecology↗