| Autor: |
Budhiraja S, Baisiwala S, Cho S, Chojak R, Kazi HA, Stepniak A, Perrault EN, Chen L, Park CH, Dmello C, Lin P, Sonabend AM, Ahmed AU |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 26. Date of Electronic Publication: 2024 Sep 26. |
| DOI: |
10.1101/2024.09.24.614748 |
| Abstrakt: |
Glioblastoma (GBM), the most common and aggressive malignant brain tumor in adults, has a median survival of 21 months. To identify drivers of GBM proliferation, 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 cells bolstered viability, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1's robust 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. Next, to understand the networks specifically regulated by THOC1-mediated R-loop prevention, we conducted unbiased RNA-sequencing on control and THOC1-knockdown GBM cells. We found 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 shows promise as a therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
