Biology subjects

Khalizeva, E.

Publications and source records attributed to Khalizeva, E..

5 recordsLinked to original sources

bioRxiv2026

5' UTR length regulates alternative N-terminal protein isoform production in health and disease

The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5' UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5' UTR length, including a deletion in the VHL 5' UTR in von Hippel-Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5' UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome. HighlightsO_LI5' UTR length affects the landscape of endogenous alternative N-terminal protein isoforms C_LIO_LIGeneration of an alternative truncated AKR7A2 isoform is mediated by short 5' UTR length C_LIO_LIAlternative transcription initiation modulates 5' UTR length to tune N-terminal isoform ratios C_LIO_LIPathogenic VHL 5' UTR variants perturb N-terminal isoform ratios by altering 5' UTR length C_LI

molecular biology↗

bioRxiv2025

mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth

MicroRNAs direct downregulation of target mRNAs. Sometimes, however, this regulatory paradigm inverts, and a target RNA triggers the degradation of a microRNA. This target-directed microRNA degradation (TDMD) requires ZSWIM8. Zswim8-/- mice exhibit reduced growth and perinatal lethality, accompanied by stabilization of dozens of microRNAs. Nonetheless, studies of TDMD function in mammals have been limited because only two TDMD-triggering RNAs have been identified in mice. Here, we computationally identify and validate five new TDMD-triggering sites in mouse models. One site in Atp6v1g1 and two in Lpar4 direct degradation of miR-335-3p, which shows that in mammals, two sites in the same transcript, and multiple sites in different transcripts, can collaborate to destabilize a microRNA. Moreover, sites in Plagl1 and Lrrc58 direct degradation of miR-322 and miR-503, respectively. Mice lacking the Plagl1 and Lrrc58 sites exhibit reduced growth, demonstrating that target-directed degradation of miR-503 and miR-322 promotes mammalian growth. Both miR-335-3p and Plagl1 are maternally imprinted, implying that they participate in parental conflict, but their corresponding triggers or target microRNA partner are not imprinted. Thus, 3' UTRs directly participate in parental conflict by engaging TDMD to access an additional layer of regulation within a network of imprinted and biallelic genes.

molecular biology↗

bioRxiv2025

SRSF12 is a primate-specific splicing factor that induces a tissue-specific gene expression program

Alternative splicing expands proteomic diversity and is tightly regulated by splicing factors, including the serine/arginine-rich (SR) protein family. Here, we analyze the poorly characterized protein SRSF12. Although SRSF12 is conserved across vertebrates, it is poorly expressed in most mammals, and we find that SRSF12 knockout mice do not display overt physiological or transcriptomic alterations. In contrast, SRSF12 is more highly expressed in primates where it is predominantly transcribed in the testes, oocytes, and brain. SRSF12 co-localizes with other splicing components to nuclear speckles and interacts with core splicing factors in cultured human cells. Strikingly, ectopic expression of SRSF12 in human cells induces widespread transcriptional changes, activating meiosis-, testis- and brain-specific genes. SRSF12 overexpression also leads to mitotic arrest and cell death, phenotypes that require both its structured RNA recognition motif and intrinsically disordered arginine/serine-rich C-terminal domain. Together, our results suggest that SRSF12 has evolved primate-specific expression to regulate testis- and brain-specific genes.

cell biology↗

bioRxiv2025

Global inhibition of deadenylation stabilizes the transcriptome in mitotic cells

In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique aspects of mitosis require substantial adaptations to the core gene expression programs. Indeed, during interphase, the homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of [~]2-4 hours. If such short mRNA half-lives persisted in mitosis, cells would be expected to quickly deplete their transcriptome in the absence of new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Typical mRNA half-lives are increased >4-fold in mitosis compared to interphase, thereby buffering mRNA levels in the absence of new synthesis. Moreover, the poly(A)-tail-length profile of mRNAs changes in mitosis, strongly suggesting a mitotic repression of deadenylation. We further show that mRNA stabilization in mitosis is dependent on cytoplasmic poly(A)-binding proteins PABPC1&4. Depletion of PABPC1&4 disrupts the maintenance of mitotic arrest, highlighting the critical physiological role of mitotic transcriptome buffering. HighlightsO_LIThe cellular transcriptome is globally stabilized during prolonged mitotic arrest C_LIO_LIDistinct poly(A)-tail-length profile of mRNAs in mitosis suggests repression of deadenylation C_LIO_LImRNA stabilization in mitosis is dependent on PABPC1 and PABPC4 C_LIO_LIDegradation of mRNAs during mitosis compromises maintenance of mitotic arrest C_LI

cell biology↗

bioRxiv2025

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease

Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function. The emergence of dual-localized mitochondrial protein isoforms coincides with mitochondrial acquisition during early eukaryotic evolution. We further reveal that eukaryotes use diverse mechanisms--such as leaky ribosome scanning, alternative transcription, and paralog duplication--to maintain the production of dual-localized isoforms. Finally, we identify multiple isoforms that are specifically dysregulated by rare disease patient mutations and demonstrate how these mutations can help explain unique clinical presentations. Together, our findings illuminate the evolutionary and pathological relevance of alternative translation initiation, offering new insights into the molecular underpinnings of mitochondrial biology.

cell biology↗