Biology subjects

Idilli, A. I.

Publications and source records attributed to Idilli, A. I..

5 recordsLinked to original sources

bioRxiv2026

MEN1 deficiency establishes a selenite-dependent binary switch in ferroptosis

Replication stress is a hallmark of cancer cells, yet the factors determining tolerance remain poorly understood. Genome-wide CRISPR screens for modifiers of replication-stress responses identified loss of the chromatin scaffold gene MEN1 as a resistance factor. We show that MEN1 deficiency suppresses lipid peroxidation and ferroptotic death, enabling survival following treatment with multiple replication stress-inducing agents. Mechanistically, MEN1 loss reduced H3.3 occupancy at ACSL1 regulatory regions and lowered ACSL1 expression, with ACSL1 loss phenocopying replication stress resistance. MEN1- or ACSL1-deficient cells also exhibited reduced levels of SLC7A11 and glutathione, rendering them hypersensitive to GPX4 inhibition under selenite-limiting conditions. Conversely, selenite supplementation preferentially increased GPX4 abundance and converted these cells to a ferroptosis-resistant state independently of SLC7A11. Thus, MEN1 links chromatin regulation to the ferroptotic control of replication stress responses, while selenite availability determines whether MEN1-deficient cells are vulnerable or resistant.

cell biology↗

bioRxiv2025

Distinct ATRX functions cooperate with 9-1-1 and CST complexesto safeguard replication and telomere integrity

Mutations in the ATRX chromatin remodeller predispose to a developmental genetic disorder and cancer, but how it safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX deficient cells. ATRX:CST synthetic lethality manifests following accumulation of telomeric G-rich ssDNA, which results in telomere loss and cell death. Conversely, we attribute ATRX:9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable requiring its ATPase activity and PIP-box, respectively, and independently of its DAXX interaction. Collectively, functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.

molecular biology↗

bioRxiv2025

SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres

The tRNA nuclease SLFN11 is epigenetically silenced in [~]50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To acquire immortality, cancer cells can activate alternative lengthening of telomeres (ALT), typically accompanied by ATRX loss. Here, we implicate SLFN11 in sensing telomere replication stress, triggering eradication of ATRX deficient cells prior to ALT establishment. Whereas progressive telomere shortening of cells lacking telomerase and ATRX leads to telomere crisis and cell death, SLFN11 loss confers tolerance to PML-BLM dependent ALT intermediates, permitting emergence of ALT survivors. We propose that during tumorigenesis SLFN11 inactivation is selected as means to tolerate endogenous replication stress following telomere crisis, leading to the development of therapy resistant tumours before treatment.

molecular biology↗

bioRxiv2025

Telomeric antisense oligonucleotides reduce premature aging phenotypes in telomerase mutant zebrafish

Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which are critical mediators of DDR activation. Blocking tncRNAs with telomeric antisense oligonucleotides (tASOs) suppresses in vivo DDR signaling and its downstream effects. Here, we show that tASO-mediated inhibition of telomeric DDR in second-generation tert-/- zebrafish embryos with critically short telomeres leads to improved developmental outcomes and rescues premature aging phenotypes, including enhanced survival. Notably, a single tASO treatment administered at the one-cell stage of first-generation tert-/- embryos leads to enhanced fertility observed in 6-month-old adults. Overall, these findings demonstrate that tASO-based inhibition of telomeric DDR is sufficient to effectively rescue premature aging phenotypes in zebrafish.

pathology↗

bioRxiv2019

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors.

The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear.\n\nHere, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks at chromosome ends. Surprisingly, expression of telomerase reverts ALT features. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed increase of telomeric heterochromatin and maintenance of telomere length compared to ALT tumors, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of telomeric DNA replication and chromatin status in brain cancers.

cancer biology↗