Toffanin, C. | bioRxiv Science

bioRxiv2026

Evolutionary insights into β-cyclocitral signaling in Physcomitrium patens

How did a product of photooxidative damage become a signal for stress tolerance? {beta}-cyclocitral ({beta}-cc) promotes acclimation in several angiosperms, yet has detrimental effects in other photosynthetic organisms. We investigated this contrast in the moss Physcomitrium patens to explore the evolution of {beta}-cc signaling. We combined apocarotenoid treatments and excess light exposure with photosynthetic measurements, biochemical analyses and RNA sequencing. Comparative phylogenomics traced the conservation of regulatory and detoxification components associated with {beta}-cc responses. Physcomitrium accumulated {beta}-cc under excess light and mounted a strong transcriptional response to exogenous {beta}-cc, substantially overlapping with its light-stress response. Nevertheless, {beta}-cc impaired photosynthetic performance and provided no protection. At a phylogenetic level, while MBS1 was deeply conserved, the downstream detoxification module showed marked divergence. Notably, ANAC081/ANAC102-like proteins were recovered in terrestrial monocots but not in Physcomitrium or Lemna turionifera, both showing detrimental responses to {beta}-cc. Our findings suggest that the evolution of protective {beta}-cc signaling involved the recruitment of downstream detoxification regulators, with the SCL14/TGAII- and ANAC081/ANAC102-related lineage emerging as a candidate link between an ancient oxidative cue and beneficial acclimation.

plant biology↗

bioRxiv2021

Therapeutic targeting of SETD2-deficient cancer cells with the small-molecule compound RITA

The histone methyltransferase SETD2 and its associated histone mark H3 lysine 36 trimethylation (H3K36me3) are frequently lost in certain cancer types, identifying SETD2 as an important therapeutic target. Here we show that SETD2-deficient cancer cells are profoundly sensitive to the compound RITA, resulting in significant p53 induction and apoptosis. This is further associated with defects in DNA replication, leading to delays in S-phase progression, increased recruitment of replication stress markers, and reduced replication fork progression. RITA sensitivity is linked to the phenol sulphotransferase SULT1A1, which we find to be highly upregulated in cells that lack SETD2. Depletion of SULT1A1 or addition of the phenol sulphotransferase inhibitor DCNP abolishes these phenotypes and suppresses the sensitivity of SETD2-deficient cancer cells, identifying SULT1A1 activity to be critical in mediating the potent cytotoxicity of RITA against SETD2-deficient cells. These findings define a novel therapeutic strategy for targeting the loss of SETD2 in cancer. Significance StatementThe histone-modifying enzyme SETD2 has emerged as an important tumour suppressor in a number of different cancer types, identifying it as a promising therapeutic target. The concept of synthetic lethality, a genetic interaction in which the simultaneous loss of two genes or pathways that regulate a common essential process renders the cell nonviable, is a valuable tool for killing cancer cells that have known mutations. In this study, we conducted a synthetic lethality screen for compounds that specifically target SETD2-deficient cancer cells. The top hit, a compound called RITA, reduces cell viability and induces cell death only in the context of SETD2 loss, thereby highlighting a potential novel therapeutic strategy for treating SETD2-deficient cancers.

cell biology↗