Biology subjects

Kristensen, S.

Publications and source records attributed to Kristensen, S..

6 recordsLinked to original sources

bioRxiv2026

ZATT/ZNF451 promotes release of stalled TOP2 cleavage complexes

Topoisomerase II (TOP2) resolves DNA topological constraints through a tightly regulated cycle of DNA double-strand cleavage and religation. Nearby DNA damage or chemotherapeutic agents such as etoposide block the DNA religation step, stabilizing TOP2-DNA cleavage complexes (TOP2ccs) at DNA double-strand breaks (DSBs). The SUMO E3 ligase ZATT (ZNF451) has recently emerged as a key effector of TOP2cc repair, but its mechanism of action remains poorly understood. Here, we show that ZATT is sufficient to resolve TOP2ccs independently of TDP2, TOP2 proteolysis, and canonical DSB repair pathways. Using Xenopus egg extracts and biochemical reconstitution, we find that ZATT salvages trapped TOP2 by promoting TOP2 release from its stalled cleavage complex. Structural modeling and targeted mutagenesis in Xenopus egg extracts and human cells identify a highly conserved hydrophobic pocket in the tower domain of TOP2 where the ZATT coiled-coil "hooks on" to promote TOP2cc resolution. Our findings reveal a new strategy to resolve TOP2ccs that bypasses the exposure of dangerous DNA breaks.

molecular biology↗

bioRxiv2025

Rab11FIP2 controls NLRP3 inflammasome activation through Rab11b

Membrane trafficking through the trans-Golgi network has recently been shown to guide activation of the NLRP3 inflammasome. The GTPases Rab11a and Rab11b, and their effector molecule Rab11-FIP2, are regulators of endosome trafficking and retrograde transport. Rab11-FIP2 binds phosphatidylinositol species including PI4P, enriched in the trans-Golgi network and peripheral endosomes following NLRP3 inflammasome activation. We here demonstrate that Rab11-FIP2 and Rab11b, but not Rab11a, control caspase-1 mediated cleavage of pro-IL-1{beta} and GSDMD, and pyroptotic cell death in human macrophages. Rab11-FIP2 also controlled LPS stimulated IKK{beta} activation by TAK1 and IKK{beta} mediated NLRP3 translocation to the trans-Golgi network. Furthermore, we show that NLRP3 bound Rab11-FIP2 via its KMKK motif and that Rab11-FIP2 interacts with NLRP3 via its N-terminal C2-domain. The formation of PI4P positive endosomes and ASC-specks were also controlled by Rab11-FIP2. Collectively our results demonstrate that Rab11-FIP2 and Rab11b control NLRP3 inflammasome activation on early endosomes in human macrophages.

immunology↗

bioRxiv2023

Contentopic mapping in ventral and dorsal association cortex: the topographical organization of manipulable object information

Understanding how object information is neurally organized is fundamental to unravel object recognition1-4. The best-known neural organizational principle of information is topographical mapping of specific dimensions. Such maps have been shown mainly for sensorimotor information within sensorimotor cortices (e.g., retinotopy)5-9. Thus, here we ask whether there are topographic maps - by analogy, contentopic maps - for mid-level object-related dimensions. We used functional magnetic resonance imaging and population receptive field analysis7 to measure tuning of neural populations to selected manipulable object-related dimensions. Here we show maps in dorsal and ventral occipital cortex that code for the score of each object on each target dimension in a linear progression following a particular direction along the cortical surface. Maps for each dimension are distinct, and consistent across individuals. Thus, object information is coded in multiple topographical maps - i.e., contentopic maps. These contentopic maps refer to intermediate level visual and visuomotor representations, and are potentially computed from the grouping of lower-level information through non-linear transformation following gestalt principles4,10. This shows that topography is a widespread and non-incidental strategy for the organization of information in the brain that leads to greatly reduced connectivity-related metabolic costs and fast and efficient readouts of information for stimuli discrimination11,12.

neuroscience↗

bioRxiv2023

Neural and behavioral signatures of the multidimensionality of manipulable object processing.

Understanding how we recognize everyday objects requires unravelling the variables that govern the way we think about objects and the way in which our representations are organized neurally. A major hypothesis is that the organization of object knowledge follows key object-related dimensions, analogously to how sensory information is organized in the brain. Here, we explored, behaviorally and neurally, the multidimensionality of object processing. We focused on within-domain object information as a proxy for the kinds of object decision tasks we typically engage in our daily lives - e.g., identifying a knife from other types of manipulable objects such as spoons, axes or screwdrivers. To do so, we extracted object-related dimensions from subjective human judgments on a set of objects from a particular object domain - i.e., manipulable objects. We demonstrated that the extracted dimensions are cognitively interpretable - i.e., participants are able to label them; are cognitively relevant for manipulable object processing - i.e., categorization decisions are guided by these dimensions; and are important for the neural organization of knowledge - i.e., they are good predictors of the neural signals elicited by manipulable objects. This shows that multidimensionality is a hallmark of the organization of object knowledge in the brain.

neuroscience↗

bioRxiv2022

Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csbm/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.

physiology↗

bioRxiv2018

Transcranial direct current stimulation alters functional network structure in humans

Transcranial direct current stimulation (tDCS) is routinely used in basic and clinical research, but its efficacy has been challenged on a methodological and statistical basis recently. The arguments against tDCS derive from insufficient understanding of how this technique interacts with brain processes physiologically. Because of its potential as a central tool in neuroscience, it is important to clarify whether and how tDCS affects neuronal activity. Here, we investigate influences of offline tDCS on network architecture measured by functional magnetic resonance imaging. Our results reveal a tDCS-induced reorganisation of a functionally-defined network that is dependent on whether we are exciting or inhibiting a node within this network, confirming in a functioning brain, and in a bias free and independent fashion that tDCS influences neuronal activity. Moreover, our results suggest that network-specific connectivity has an important role in defining the effects of tDCS and the relationship between brain states and behaviour.

neuroscience↗