Abuhussein, O. | Search bioRxiv

bioRxiv2025

Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers

Telomerase reverse transcriptase (hTERT) overexpression, a hallmark of most cancers, drives tumorigenesis by enabling limitless replicative potential. Direct targeting of hTERT is challenging, necessitating alternative strategies. Through genome-wide synthetic dosage lethality (SDL) screening in cancer models, including patient-derived organoids, we identify FTSJ3, an RNA 2-O-methyltransferase, as a critical vulnerability in hTERT-overexpressing cells. FTSJ3 methylates telomeric repeat-containing RNA (TERRA), a modification essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts this cascade, impairing H3K9 trimethylation, HP1-alpha recruitment, and telomeric heterochromatin maintenance. Notably, this reveals an unexpected dependency on TERRA methylation for telomeric heterochromatin stability in hTERT-driven cancers. Non-malignant cells, lacking telomerase activity and de novo telomere repeat synthesis, are unaffected by FTSJ3 suppression. Our findings establish the FTSJ3/TERRA/SUV39H1 axis as a critical mechanism supporting telomeric heterochromatin stability in hTERT-driven cancers. This telomere-directed epigenetic strategy provides a robust framework for translational therapeutic innovation.

cancer biology↗

bioRxiv2024

Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Tumor heterogeneity poses a significant challenge in combating treatment resistance. Despite Polo-like kinase 1 (PLK1) being universally overexpressed in cancers and contributing to chromosomal instability (CIN), direct PLK1 inhibition hasnt yielded clinical progress. To address this, we utilized the synthetic dosage lethality (SDL) approach, targeting PLK1s genetic interactions for selective killing of overexpressed tumor cells while mitigating heterogeneity-associated challenges. Employing computational methods, we conducted a genome-wide shRNA screen, identifying 105 SDL candidates. Further in vivo CRISPR screening in a breast cancer xenograft model and in vitro CRISPR analysis validated these candidates. Employing Perturb-seq revealed IGF2BP2/IMP2 as a key SDL hit eliminating PLK1-overexpressing cells. Suppression of IGF2BP2, genetically or pharmacologically, downregulated PLK1 and limited tumor growth. Our findings strongly propose targeting PLK1s genetic interactions as a promising therapeutic approach, holding broad implications across multiple cancers where PLK1 is overexpressed.

cancer biology↗