Biology subjects

Brom, T.

Publications and source records attributed to Brom, T..

5 recordsLinked to original sources

bioRxiv2025

The NAT10 acetyltransferase modulates DNA damage-related factors and global 3D-genome architecture

We explored the role of NAT10 acetyltransferase in the DNA damage response, focusing on its impact on 3D-genome architecture and DNA repair proteins. Compared to NAT10 wild-type (wt), NAT10 deficiency reduced XPC, DDB2, and p53 protein levels. In TP53 double-null (dn) cells, the NAT10 protein was undetectable, and DDB2 was significantly down-regulated. Although NAT10 depletion caused DDB2 down-regulation, it did not affect the DNA repair functions of the DDB2 protein. To this fact, protein interaction analysis revealed that UVC exposure weakens the DDB2-p53 interaction while strengthening the bond between NAT10 and DDB2. Also, AlphaFold 3 prediction tools showed a more potent interaction between DDB2 and p53 than DDB2 and NAT10 proteins implying that NAT10 rather regulates the DDB2-p53 protein complex. These proteomic NAT10-dependent changes coincided with alterations in chromatin interactions, particularly in acrocentric chromosomes, studied by the Hi-C technique. However, 3D-genome rearrangement, caused by NAT10 deficiency and UVC irradiation, did not significantly impact post-translational histone modifications. Overall, NAT10 depletion alters the pool of key DNA repair proteins and induces substantial 3D-genome reorganization. Graphical abstractThe effect of the NAT10 acetyltransferase depletion and UVC irradiation on 3D-genome nuclear architecture, histone signature, and the pool of selected DNA repair-related proteins. The figure was made using some icons adapted from BioRender software.

cell biology↗

bioRxiv2023

Structural insights into inherited anemia CDA-I: disease-associated mutations disrupt CDIN1-Codanin1 complex

Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease marked by ineffective erythropoiesis, a characteristic spongy heterochromatin structure in erythroblasts, and mutations in the genes CDAN1 and CDIN1, which encode the proteins Codanin1 and CDIN1. Codanin1 regulates histone shuttling via the chaperone ASF1, yet the role of CDIN1 in CDA-I pathology remains unclear. Notably, CDIN1 is known to interact directly with the C-terminus of Codanin1. Although mutations in both genes are critical to the disease phenotype, their molecular-level effects have not been fully elucidated. Here, we present a comprehensive structural and functional analysis of the CDIN1-Codanin1 C-terminus complex. Using complementary biophysical techniques, we show that CDIN1 and Codanin1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. We further delineate the essential interacting regions of CDIN1 and Codanin1. We demonstrate that CDA-I-associated mutations in either protein disrupt CDIN1-Codanin1 interaction, suggesting a potential molecular mechanism underlying the disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/542057v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ca4364org.highwire.dtl.DTLVardef@e74ccorg.highwire.dtl.DTLVardef@1160f92org.highwire.dtl.DTLVardef@158536b_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Electron microscopy reveals toroidal shape of master neuronal cell differentiator REST - RE1-Silencing Transcription factor

The RE1-Silencing Transcription factor (REST) is essential for neuronal differentiation. Here, we report the first 18.5-angstrom electron microscopy structure of human REST. The refined electron map suggests that REST forms a torus that can accommodate DNA double-helix in the central hole. Additionally, we quantitatively described REST binding to the canonical DNA sequence of the neuron-restrictive silencer element. We developed protocols for the expression and purification of full-length REST and the shortened variant REST-N62 produced by alternative splicing. We tested the mutual interaction of full-length REST and the splicing variant REST-N62. Revealed structure-function relationships of master neuronal repressor REST will allow finding new biological ways of prevention and treatment of neurodegenerative disorders and diseases.

biochemistry↗

bioRxiv2021

Balancing selection and the crossing of fitness valleys in structured populations: diversification in the gametophytic self-incompatibility system

The self-incompatibility locus (S-locus) of flowering plants displays a striking allelic diversity. How such a diversity has emerged remains unclear. In this paper, we performed numerical simulations in a finite island population genetics model to investigate how population subdivision affects the diversification process at a S-locus, given that the two-genes architecture typical of S-loci involves the crossing of a fitness valley. We show that population structure slightly reduces the parameter range allowing for the diversification of self-incompatibility haplotypes (S-haplotypes), but at the same time also increases the number of these haplotypes maintained in the whole metapopulation. This increase is partly due to a higher rate of diversification and replacement of S-haplotypes within and among demes. We also show that the two-genes architecture leads to a higher diversity in structured populations compared with a simpler genetic architecture where new S-haplotypes appear in a single mutation step. Overall, our results suggest that population subdivision can act in two opposite directions: it renders S-haplotypes diversification easier, although it also increases the risk that the self-incompatibility system is lost.

evolutionary biology↗

bioRxiv2018

Breakdown of gametophytic self-incompatibility in subdivided populations

Many hermaphroditic flowering plants species possess a genetic self-incompatibility (SI) system that prevents self-fertilization and is typically controlled by a single multiallelic locus, the S-locus. The conditions under which SI can be stably maintained in single isolated populations are well known and depend chiefly on the level of inbreeding depression and the number of SI alleles segregating at the S-locus. However, while both the number of SI alleles and the level of inbreeding depression are potentially affected by population subdivision, the conditions for the maintenance of SI in subdivided populations remain to be studied. In this paper, we combine analytical predictions and two different individual-based simulation models to show that population subdivision can severely compromise the maintenance of SI. Under the conditions we explored, this effect is mainly driven by the decrease of the local diversity of SI alleles rather than by a change in the dynamics of inbreeding depression. We discuss the implications of our results for the interpretation of empirical data on the loss of SI in natural populations.\n\nData accessibility statementNo data to be archived

evolutionary biology↗