# THOC1 complexes with SIN3A to regulate R-loops and promote glioblastoma progression

## TL;DR

THOC1 promotes glioblastoma growth by regulating R-loops and telomere stability, making it a potential target for treatment.

## Contribution

THOC1 is identified as a novel driver of glioblastoma progression through its role in R-loop regulation and telomere stability.

## Key findings

- THOC1 interacts with SIN3A to control R-loop homeostasis in glioblastoma cells.
- THOC1 loss increases R-loops and disrupts telomere stability, reducing GBM viability.
- Targeting THOC1 impairs GBM growth in patient-derived xenograft models.

## Abstract

•CRISPR screen identifies THOC1 as a GBM progression driver•THOC1 complexes with SIN3A to control R-loop homeostasis•THOC1 loss increases R-loops and disrupts telomere stability•Targeting THOC1 impairs GBM viability in PDX models•THOC1 is a promising therapeutic vulnerability in GBM

CRISPR screen identifies THOC1 as a GBM progression driver

THOC1 complexes with SIN3A to control R-loop homeostasis

THOC1 loss increases R-loops and disrupts telomere stability

Targeting THOC1 impairs GBM viability in PDX models

THOC1 is a promising therapeutic vulnerability in GBM

Glioblastoma (GBM), the most common and aggressive primary malignant brain tumor in adults, has a median survival of 14.6 months. To identify drivers of GBM pathogenesis, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous neural stem cells bolstered transformation capacity, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1′s interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. RNA-sequencing analysis revealed that THOC1’s role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 is a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.

Glioblastoma, the most aggressive malignant brain tumor in adults, relies on a delicate R-loop landscape to promote cell replication while avoiding DNA damage. Targeting THOC1 represents a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.