Biology subjects

Szabo, T.

Publications and source records attributed to Szabo, T..

3 recordsLinked to original sources

bioRxiv2024

Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment

Neomorphic mutations and drugs can elicit unanticipated effects that hinder mechanistic understanding for clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. Remarkably, UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. We identified that these neomorphic interactions were mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 captured 2:1 and 2:2 KBTBD4-HDAC2 complexes at resolutions spanning 2.7 [A] to 3.1 [A]. The mutant and drug-induced complexes adopted similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 was identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshaped the same surface of KBTBD4 providing the first example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4 and help to explain the structure-activity relationships of UM171 derivatives for future drug design.

molecular biology↗

bioRxiv2024

The interaction of relative age with maturation and body size in female handball talent selection based on only sport-specific criteria

Talent identification is often affected by the relative age effects (RAEs) and/or maturation. Previous research has suggested that talent selection should include sport-specific technical tasks instead of body size and/or physical test measurements, assuming that the technical tasks are less influenced by interindividual variability in maturation. Our purpose was to examine the prevalence of RAEs and how biological maturity, body size, and body composition in relation to relative age affect talent selection among female handball players. Handball-specific drills and in-game performance were the criteria of a single talent selection program. Birth distribution of U14 female (N = 3198) handball players were analyzed. Body size, body composition, and bone age were assessed on 264 selected and 266 not-selected players. Body composition was assessed with InBody 720, whereas biological age from bone age. Chi-square was used to examine quartile distributions, and logistic regression to determine the effects of the predictors on the selection. In terms of all registered players, there was no difference in birth distribution. RAEs appeared at the first selection level and were evident at all levels. Quartiles differed only between the first and the last quartiles in body size and muscle mass. Only bone age differed between consecutive quartile or semi-year groups. Body size, body composition, and maturity had a significant, but of moderate power, effect on the selection. Larger body height increased selection odds by about 12%, larger muscle mass by 12% to 25%, larger percent body fat decreased selection odds by 7%, while larger bone age by 3.5-4 times. RAEs affected talent selection when applying sport-specific drills as selection criteria. Relative age was connected to bone age, but not convincingly to body size and muscle mass. Bone age had the largest effect on the selection, but this was not associated with larger body size or muscle mass.

physiology↗

bioRxiv2022

The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

Pleiotropic functions of miRNAs as transcriptional repressors have been reported for multiple biological processes. One prominent miRNA family is the miR-15 family, which is a well-established tumor-suppressor in B-cell chronic lymphocytic leukemia (CLL). The miR-15 family consists of three bicistronic clusters, miR-15a/16-1, miR-15b/16-2 and miR-497/195, all sharing the same seed sequence suggesting that loss one cluster can be functionally compensated by the remaining miR-15 family members. Thus, a combined deletion may be necessary to reveal its physiological function in vivo. A combined knockout of the most prominent miR-15 clusters, miR-15a/16-1 and miR-15b/16-2 in the hematopoietic system reveals a novel role of the miR-15 family in early B cell development highlighted by an increase of the pro-B cell compartment. Mechanistically, this effect is mediated by enhanced IL-7 receptor expression, which we identified as direct miR-15 target gene. Notably, elevated IL-7 receptor levels were sufficient to trigger increased activation of the STAT5 and PI3K/AKT pathways. Moreover, derepression of directly targeted cell cycle regulators such as Ccne1, Chek1 and Wee1 further facilitates G-to-S transition. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu manifesting in an enlarged pro-B cell pool.

immunology↗