Biology subjects

Mendoza-Figueroa, M. S.

Publications and source records attributed to Mendoza-Figueroa, M. S..

3 recordsLinked to original sources

bioRxiv2025

Defining the impact of rRNA processing on nucleolar organization and function

The eukaryotic nucleolus is a highly organized, multilayered structure essential for ribosomal RNA (rRNA) processing and ribosome assembly. However, how the sequential steps of rRNA maturation, particularly the series of endonucleolytic cleavages, contribute to maintaining nucleolar architecture remains poorly understood. Here, we show that disruption of pre-rRNA processing, especially impaired cleavage of the 5' external transcribed spacer (5'ETS), profoundly alters nucleolar organization. Specifically, defects in 5'ETS processing lead to the formation of a single large DAPI-negative nuclear structure and result in the mislocalization of nascent RNA, which diffuses throughout the disorganized nucleolus. These aberrant nucleoli exhibit a distinct proteomic profile, including downregulation of factors involved in splicing, cell cycle regulation, and chromatin organization, suggesting that the impact of nucleolar disorganization extends beyond ribosome biogenesis. Notably, we also observe mislocalization of heterochromatin markers, pointing to broader disruptions in nuclear architecture and gene regulation. Together, our findings reveal that proper 5'ETS cleavage is critical for preserving nucleolar compartmentalization and highlight the tight coupling between rRNA processing and nuclear organization.

molecular biology↗

bioRxiv2024

Leukemia-mutated proteins PHF6 and PHIP form a chromatin complex that represses myeloid leukemia stemness

Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly-understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). PHF6 mutations are associated with poorer outcomes, while PHIP was recently identified as the most common selective mutation in Black patients in AML. Here, we show that PHF6 is a transcriptional repressor that suppresses a stemness gene network, and that PHF6 missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or non-functional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.

cancer biology↗

bioRxiv2023

IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events

The metazoan-specific Integrator complex catalyzes 3 end processing of small nuclear RNAs (snRNAs) as well as premature transcription termination events that attenuate expression of many protein-coding genes. Integrator has RNA endonuclease and protein phosphatase activities, but it remains unclear if both are always required for complex function. Here, we show that IntS6 (Integrator subunit 6) over-expression is sufficient to block Integrator function at a subset of Drosophila protein-coding genes, while having no effect on snRNA processing or attenuation of other loci. Over-expressed IntS6 titrates protein phosphatase 2A (PP2A) subunits from the rest of the Integrator complex and thus the only loci affected are those where the phosphatase module is necessary for Integrator function. IntS6 functions analogous to a PP2A regulatory B subunit as over-expression of canonical B subunits, which do not associate with Integrator, are also sufficient to inhibit Integrator function at select loci. Altogether, these results show that the phosphatase module is critical and limiting at only a subset of Integrator regulated genes and point to recruitment of PP2A via IntS6 as a tunable step that can be used to modulate transcription termination efficiency.

molecular biology↗