Biology subjects

Karadimov, G.

Publications and source records attributed to Karadimov, G..

3 recordsLinked to original sources

bioRxiv2025

The CENP-A chaperone complex spatially organizes centromeres

Centromeres, defined by CENP-A-containing nucleosomes, direct the assembly of kinetochores for spindle attachment. In mitosis, CENP-A and the constitutive centromere-associated network (CCAN) of the inner kinetochore are arranged into bipartite subdomains within clearings of chromatin. However, it remains unclear whether any of these features exist before mitosis. We show that in interphase, CENP-A and the CCAN assemble [~]200-300 nm shell-like structures that enclose a chromatin-poor central cavity. Strikingly, this cavity is occupied by the interphase-specific CENP-A chaperone complex, which promotes CENP-A assembly once per cell cycle. However, chaperone presence, but not CENP-A incorporation, is required to generate both the shell architecture and the chromatin clearing. The CCAN scaffold CENP-C, which links CENP-A nucleosomes to the chaperone complex, exhibits radial organization spanning the entire structure and is essential for its formation. These data uncover a previously unrecognized structural role for the CENP-A chaperone machinery in establishing interphase centromere architecture and suggest a mechanism by which this machinery configures centromeres for faithful kinetochore assembly and genome stability.

cell biology↗

bioRxiv2024

Translation Initiation Represents an Acute Myeloid Leukemia Cell Vulnerability That Can Be Co-Targeted With BCL-2 Inhibition

Targeted therapies like Venetoclax have increased the options available to acute myeloid leukemia (AML) patients, but survival remains poor due to drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex mRNA structures in the 5 UTR of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells. Inhibiting eIF4A with the small molecule Zotatifin reduces translation of transcripts related to the cell cycle and survival. This results in downregulation of AKT, STAT-5, and MCL-1 and underlies synergy of Zotatifin with Venetoclax. The drug combination promotes apoptosis across AML genotypes, while the effect on healthy blood cells is limited. Using in vivo relapsed and refractory AML patient-derived xenograft models, the combination significantly suppressed tumor burden and prolonged survival of xenografted mice. These results support eIF4A-mediated protein translation as a therapeutic target in AML. SIGNIFICANCEDespite advances in targeted therapies, the 5-year survival rate for acute myeloid leukemia remains around 32%. The efficacy of existing treatments may be improved with the addition of Zotatifin, an inhibitor targeting the translation initiation factor eIF4A.

cancer biology↗

bioRxiv2024

Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut) and 1p/19q co-deletions. Previously, we reported that in IDH1mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDHmut-specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1mut oligodendroglioma. We demonstrated an IDH1mut-specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1mut and should be considered in the future.

cancer biology↗