Biology subjects

de Koning, K.

Publications and source records attributed to de Koning, K..

3 recordsLinked to original sources

bioRxiv2024

FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments

Homologous recombination (HR) deficiency upon BRCA2 loss arises from defects in the formation of RAD51 nucleoprotein filaments. Here, we demonstrate that loss of the anti-recombinase FIGNL1 retains RAD51 loading at DNA double-stranded breaks (DSBs) in BRCA2-deficient cells, leading to genome stability, HR proficiency, and viability of BRCA2-deficient mouse embryonic stem cells. Mechanistically, we directly show that strand invasion and subsequent HR defects upon BRCA2 loss primarily arises from the unrestricted removal of RAD51 from DSB sites by FIGNL1, rather than from defective RAD51 loading. Furthermore, we identify that the MMS22L-TONSL complex interacts with FIGNL1 and is critical for HR in BRCA2/FIGNL1 double-deficient cells. These findings identify a pathway for tightly regulating RAD51 activity to promote efficient HR, offering insights into mechanisms of chemoresistance in BRCA2-deficient tumors.

genetics↗

bioRxiv2024

TwinEco: A Unified Framework for Dynamic Data-Driven Digital Twins in Ecology

1.A Digital Twin (DT) is a virtual replica of a physical object or process that is continuously updated at a certain frequency and can steer change on the physical system, enabling a seamless integration of observation, understanding, and action. Although initially applied primarily in industry, DT is emerging as a powerful tool in ecology, offering new possibilities for dynamic simulations of change in the biosphere. However, since DTs are relatively new in this field, there is currently no standard framework to guide their conceptualisation and development. Thus, DTs in ecological applications are already experiencing fragmentation in software concepts and design philosophies, leading to incompatibilities across DT implementations. This fragmentation risks undermining the progress and potential of the DT concept in ecology. A unifying framework, such as TwinEco, can address these discrepancies and establish a cohesive foundation for the effective adoption and integration of DTs across ecological domains. TwinEco is a modular framework designed to aid and harmonise ecologists efforts to build DTs. In doing so, TwinEco focuses on three major design goals: O_LIModularity, flexibility, and interoperability of DTs facilitated through distinct "components" nested within DT "layers". C_LIO_LIDynamic modeling of ecological processes and states that evolve over time. C_LIO_LILinking ecological modelling to downstream actions or decisions made on the ecological object or process of study. C_LI TwinEcos architecture builds upon the feedback loops and state management strategies introduced in the Dynamic Data-Driven Application Systems (DDDAS) paradigm, which has already inspired many DTs across scientific domains. We also discuss the usefulness and ease-of-use of TwinEco by demonstrating its applicability to computational case studies and suggesting future recommendations to the community of data infrastructure builders and modellers in regards to open considerations. By introducing a shared terminology and emphasising model-data fusion, TwinEco highlights the importance of a unified framework to avoid fragmentation in the burgeoning field of ecological digital twinning.

ecology↗

bioRxiv2021

Experimental evidence for enhanced receptor binding by rapidly spreading SARS-CoV-2 variants

Rapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 9-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation does not significantly influence the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 3-fold weaker than N501Y. The recently emerging double mutant E484K/N501Y binds as tight as N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.

biochemistry↗