Palmero, I. | bioRxiv Science

bioRxiv2026

The resolvin D and E biogenesis pathway regulatessenescence and ageing

Ageing is considered as a process were molecular, cellular and tissular function is impaired. One classic cellular phenotype that increases during ageing is cellular senescence. Upon senescence, the cells stop proliferating and release a variety of cytokines, chemokines and extracellular vesicles. However, the implication of biomolecules derived from lipids such as resolvins are not well characterised in senescence and ageing. Here, we find that the resolvin E and D biosynthesis pathway is activated as observed by an increase in their corresponding receptors and enzymes implicated. Furthermore, knockdown of the resolvins E and D receptors impairs the induction of senescence. This pathway is conserved not only during senescence but also in fibroblasts derived from aged human individuals, aged mice and during other inflammatory responses. A metabolomics analyses shows an increase in different precursors of resolvins in senescence. In accordance with prior data, we find that small extracellular vesicles (sEV) isolated from young human donors ameliorate inflammation and the biogenesis of resolvins both in different cell models and in aged mice. In summary, here we present data showing that the resolvins biogenesis pathway is induced in ageing and cellular senescence.

cell biology↗

bioRxiv2024

The signaling axis CDK12-BRCA1 mediates dinaciclib associated radiosensitivity through p53-mediated cellular senescence.

Pan-CDK inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as monotherapy, an interesting approach could be to combine it with radiotherapy. Here we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter responses such as ATM signalling, apoptosis or cell cycle profiling after ionising radiation exposure that have been described for other CDK inhibitors. Mechanistically, inhibition of CDK12 by dinaciclib abolishes BRCA1 expression, which blocks homologous recombination (HR), leaving only the non-homologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising radiation-associated cellular senescence in a p53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report explains the molecular mechanism involved in this novel therapeutic effect of dinaciclib and provides a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour. Highlights[tpltrtarr] Dinaciclib is a radiosensitising agent in lung and colon cancer cell lines. [tpltrtarr]Dinaciclib promotes radiosensitivity by inhibiting CDK12 leading to a decrease in BRCA1 expression. [tpltrtarr]Lack of BRCA1 blocks homologous recombination response to DNA damage, enhancing ionising radiation-associated senescence in a p53-dependent fashion. [tpltrtarr]The combination of dinaciclib plus radiotherapy could be a novel treatment for tumours holding functional BRCA1 and p53 signalling.

cancer biology↗