Biology subjects

Lingg, L.

Publications and source records attributed to Lingg, L..

4 recordsLinked to original sources

bioRxiv2026

Aurora kinase A is a synthetic lethal target in FANCA-deficient cancers

Loss-of-function genomic alterations in FANCA occur across multiple cancer types, yet no molecularly tailored therapies have successfully exploited this potential vulnerability. Using complementary unbiased approaches, including a genome-wide CRISPR/Cas9 loss-of-function screen and a high-throughput drug screen in isogenic cancer cell-based models, we identified Aurora kinase A (AURKA) as a reproducible synthetic lethal target of FANCA-deficient cancers. Inhibition of AURKA induced chromosomal instability, micronucleation, and early G2/M arrest selectively in FANCA-deficient cells, consistent with an increased reliance on mitotic checkpoint control. Mechanistically, FANCA deficiency is associated with an elevated AURKA expression at both the transcriptomic and protein levels, and with an upregulation of mitotic spindle and G2/M checkpoint gene signatures. Analysis of large-scale cancer genomics datasets, including over 650,000 clinically sequenced tumors, confirms that FANCA is the most frequently altered Fanconi anemia pathway gene across cancers, and that Fanconi anemia-defective tumors exhibit an increased tumor mutational burden and genomic instability. Collectively, our findings point to AURKA inhibition as a promising precision treatment strategy in FANCA-deficient cancers and provide a rationale to further explore this strategy in the clinic.

cancer biology↗

bioRxiv2025

Blocking Minor Intron Splicing Disrupts DNA Repair and Overcomes Therapy Resistance in Prostate and Breast Cancer

The minor spliceosome (MiS) is a specialized RNA-processing machinery upregulated in cancer, promoting oncogene expression. We uncovered an adaptive resistance mechanism driven by secretion of extracellular vesicles enriched in U6atac snRNA, which amplifies MiS activity and promotes therapy resistance. Here, we show that U6atac snRNA, a crucial MiS component, reverses this process when depleted, revealing it as a druggable vulnerability in therapy-resistant prostate and breast cancers. U6atac knockdown triggers R-loop-mediated DNA damage while impairing repair by downregulating key DNA repair factors, disabling both homologous recombination and non-homologous end joining. This dual effect sensitizes prostate and breast tumors to PARP inhibitors, cisplatin, and radiation, independent of BRCA status. Across multiple in vitro and in vivo models, MiS targeting demonstrates tumor-selective activity with minimal toxicity. These findings position U6atac as a central regulator of genome stability and establish MiS targeting as a promising approach to potentiate genotoxic therapy and overcome resistance. Statement of significanceU6atac, a minor spliceosome component, is a crucial regulator of genome stability in cancer. Its knockdown triggers R-loop-driven DNA damage, downregulates DNA repair genes, and sensitizes tumors to DNA-damaging therapies while simultaneously blocking resistance mechanisms. Thus, minor spliceosome knockdown is a tumour-selective and broadly applicable therapeutic strategy.

cancer biology↗

bioRxiv2025

TAOK1 regulates chemo- and radiosensitivity in BRCA1/2-deficient tumors

BRCA1/2-deficient cells are hypersensitive to replication stress- and DNA-damage-inducing agents such as poly(ADP-ribose) polymerase inhibitors (PARPi), platinum drugs, and ionizing radiation (IR), largely due to impaired homologous recombination repair and replication fork (RF) protection. The precise mechanisms underlying RF vulnerability in the absence of BRCA1/2 remain incompletely understood, however. Here, we identify Thousand And One Amino Acid Kinase 1 (TAOK1) as a novel regulator of RF dynamics that sensitizes BRCA1/2-deficient cells to both PARPi and IR. Unlike established DNA repair factors, such as PARG or the 53BP1-RIF1-shieldin-CST pathway, which mediate PARPi sensitivity while protecting cells against IR, TAOK1 promotes RF degradation and suppresses post-replicative damage repair. TAOK1 depletion stabilizes RFs and reduces replication-associated DNA damage in BRCA1/2-deficient cells, thereby conferring therapy resistance. Interestingly, we found that TAOK1 functions in RF regulation to be independent of its kinase activity. Instead, it interacts with PCNA and regulates ISG15 levels and thereby affects RF stability. Our findings reveal TAOK1 as a non-canonical mediator of therapy sensitivity in BRCA1/2-deficient tumors. TeaserTAOK1 controls replication fork stability through PCNA and ISG15, affecting therapy response in BRCA1/2-deficient cancers.

cancer biology↗

bioRxiv2022

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). PSMC3IP or MND1 depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage.

cancer biology↗