Biology subjects

Dulac, L.

Publications and source records attributed to Dulac, L..

3 recordsLinked to original sources

bioRxiv2025

Developmental senescence profiling reveals Eda2r as a common mediator in the core senescence program

Cellular senescence is a distinct state of stable cell-cycle arrest coupled to a dynamic secretory phenotype. Although transient senescence contributes to embryonic development and regeneration, its relationship to the chronic forms associated with damage and aging is unclear. Here, we generated a p21-reporter mouse to isolate and transcriptionally profile senescent cells in Apical Ectodermal Ridge of the developing limb. Comparative analysis of these cells with diverse in vitro and in vivo senescence models revealed a conserved gene program encompassing canonical markers and regulators, with previously unassociated factors. Among these, ectodysplasin A2 receptor (Eda2r) emerged as a critical modulator required for senescence-associated transcriptional and functional features. Our findings define a shared molecular framework linking developmental and pathological senescence and identify conserved effectors such as Eda2r as potential targets for therapeutic modulation of senescent cell function.

cell biology↗

bioRxiv2025

Senescent cells exhibit features of developmental signaling centres

Cellular senescence is a state that contributes to tissue patterning during development and tissue repair, but which becomes misregulated in ageing and disease. The senescence-associated secretory phenotype (SASP) mediates many of the context-dependent effects, yet its molecular composition and evolutionary origins remain incompletely understood. Here, we characterize the SASP signature of developmental senescent cells and find that it is enriched for genes encoding major developmental signaling pathways. Integrative analyses of in vitro and in vivo transcriptomes reveal that human and mouse senescent cells across diverse contexts consistently activate these developmental programs, with key morphogens constituting conserved SASP components. Functionally, we show that the SASP is sufficient to induce the expression of central developmental genes and transcription factors across multiple cell types. These findings show that senescent cells resemble developmental signaling centers and uncover developmental signaling reactivation as an evolutionarily conserved feature of senescence, providing conceptual insight into its physiological functions and its pathological impact during ageing.

cell biology↗

bioRxiv2022

Specific conformational dynamics of the ATPase head domains and DNA exit gate mediate the Cohesin ATPase cycle

Cohesin is key to eukaryotic genome organization and acts throughout the cell cycle in an ATP- dependent manner. The molecular mechanisms underlying the Cohesin ATPase activity are poorly understood. Here, we have characterized distinct steps of the human Cohesin ATPase cycle and show that the SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements along this cycle. Specifically, while the proximal coiled coil of the SMC1A ATPase domain remains conformationally stable, that of SMC3 displays an intrinsic flexibility. The ATP-dependent formation of the heterodimeric SMC1A/SMC3 ATPase module (engaged state) favours this flexibility, while it is counteracted by binding of NIPBL and DNA (clamped state). Opening of the SMC3/RAD21 interface (open-engaged state) leads to a stiffening of the SMC3 proximal coiled coil that constricts, together with that of SMC1A, the DNA binding chamber of the ATPase module. Our results reveal that the plasticity of the ATP-dependent interface between the SMC1A and SMC3 ATPase domains enables the structural rearrangements occurring between the engaged, clamped and open-engaged states, while keeping the ATP gate shut.

biochemistry↗