Astrid Deschênes

Molecular properties of human diseases and conditions often exhibit dependence on the genetic ancestry of the donor. In order to make more human molecular data available for ancestry-informed research, we developed a set of software tools termed Robust Ancestry Inference using Data Synthesis (RAIDS) for inference of genetic ancestry from sequence data that pose challenges to genotyping. Here we describe a recent expansion and refinement of RAIDS, applicable to nucleic-acid sequence data resultant from a broad range of experimental strategies. These strategies currently include whole-genome, whole-exome, and targeted gene panel sequencing, RNA-Seq, including single-cell RNA-Seq, chromatin-accessibility (ATAC-Seq), and protein-binding (ChIP-Seq) assays. RAIDS inferential tools perform robustly in the presence of somatic nucleic-acid alterations caused by cancer and under the conditions of extreme non-uniformity of sequence read coverage, yielding both global ancestry and ancestral admixtures of the donor. RAIDS is available as an eponymous Bioconductor package.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor serine/arginine-rich splicing factor 1 (SRSF1) plays a key oncogenic role in PDAC through reciprocal cross-interactions with KRAS signaling. However, the mechanisms regulating SRSF1 protein stability remain poorly understood. In this study, we identify the deubiquitinase USP39 as a critical regulator of SRSF1 stability. It interacts with SRSF1 in an RNA-independent manner and suppresses its ubiquitination. USP39 is upregulated in PDAC and correlates with poor patient prognosis. Functional analyses demonstrate that USP39 promotes PDAC cell progression, in part through the stabilization of SRSF1. Mechanistically, MYC activates USP39 transcription through direct promoter binding. These findings define a MYC–USP39–SRSF1 regulatory axis that integrates transcriptional and posttranslational mechanisms in PDAC and suggest USP39 as a potential therapeutic target. Implications:USP39 functions as a central regulator that integrates transcriptional and posttranslational regulation in pancreatic cancer through the MYC–USP39–SRSF1 axis and represents a potential therapeutic target.

SRSF1 expression is increased upon pharmacological inhibition of RNA splicing.

SRSF1 protein levels remain unchanged following knockdown of USP9X or USP10.

USP39 knockdown suppresses PDAC tumor cells division.

SRSF1 knockdown suppresses PDAC lung metastasis.

MYC binds to the USP39 promoter.

Proteins associated with the ubiquitin–proteasome pathway identified by proximity labeling.

USP39 knockdown decreases SRSF1 expression in subcutaneous xenografts.

Table S1 from MYC-Mediated USP39 Upregulation Stabilizes SRSF1 in Pancreatic Cancer