Biology subjects

Merens, H. E.

Publications and source records attributed to Merens, H. E..

3 recordsLinked to original sources

bioRxiv2026

SRSF1 regulates polyadenylation site selection independently of and through coordination with U1 snRNP

Proper polyadenylation site (PAS) selection is critical for RNA isoform determination. Core spliceosomal components, including U1 snRNP, regulate PAS choice, but whether they work with other splicing factors in this role remains unclear. Here, we establish that the splicing factor SRSF1 regulates 3'-end selection through complementary mechanisms with varying degrees of independence from U1 snRNP. Within 3 UTRs, largely independent of U1 snRNP, SRSF1 binds RNA near proximal PASs and promotes their usage. Congruent with this observation, breast cancer tumors with altered SRSF1 levels display shifted 3'-end selection. At PASs modulated by both SRSF1 and U1 snRNP, SRSF1 acts on sites through U1 snRNP-mediated Pol II interactions. Consistent with co-transcriptional regulation, SRSF1 reduces the Pol II elongation index and transcription readthrough. Together, our results reveal that SRSF1 shapes RNA isoform determination beyond its canonical role in splicing, through a combination of direct RNA binding and U1 snRNP-dependent co-transcriptional coordination.

molecular biology↗

bioRxiv2023

Genome-wide screens for mitonuclear co-regulators uncover links between compartmentalized metabolism and mitochondrial gene expression

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells, in which gene expression must be coordinated across organelles using distinct pools of ribosomes. How cells produce and maintain the accurate subunit stoichiometries for these OXPHOS complexes remains largely unknown. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of cytochrome c oxidase (Complex IV). We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically regulates Complex IV biogenesis by interacting with mitochondrial protein synthesis machinery, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS complex biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 maintains local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, through stabilizing interactions with RCC1L, NME6 modulates the activity of mitoribosome regulatory complexes, leading to disruptions in mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression. Finally, we present these screens as a resource, providing a catalog of genes involved in mitonuclear gene regulation and OXPHOS biogenesis.

molecular biology↗

bioRxiv2019

Polyphosphate initiates tau aggregation through intra- and intermolecular scaffolding

The aggregation and deposition of tau is a hallmark of a class of neurodegenerative diseases called tauopathies. Despite intensive study, cellular and molecular factors that trigger tau aggregation are not well understood. Here we provide evidence for two mechanisms relevant to the initiation of tau aggregation in the presence of cytoplasmic polyphosphates (polyP): changes in the conformational ensemble of monomer tau and noncovalent cross-linking of multiple tau monomers. We identified conformational changes throughout full-length tau, most notably diminishment of long-range interactions between the termini coupled with compaction of the microtubule binding and proline rich regions. We found that while the proline rich and microtubule binding regions both contain polyP binding sites, the proline rich region is a requisite for compaction of the microtubule binding region upon binding. Additionally, both the magnitude of the conformational change and the aggregation of tau are dependent on the chain length of the polyP polymer. Longer polyP chains are more effective at intermolecular, noncovalent cross-linking of tau. These observations provide an understanding of the initial steps of tau aggregation through interaction with a physiologically relevant aggregation inducer.

biophysics↗