Biology subjects

Pruvost, A.

Publications and source records attributed to Pruvost, A..

3 recordsLinked to original sources

bioRxiv2021

TRIM28-dependent SUMOylation protects the adult ovary from the male pathway

Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. In the mouse ovary, oestrogen receptors and FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying their protective effect is unknown. Here, we show that TRIM28 is required to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of Trim28, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type, different from gonadal embryonic progenitors. TRIM28 is recruited on chromatin in the proximity of FOXL2 to maintain the ovarian pathway and to repress testicular-specific genes. The role of TRIM28 in ovarian maintenance depends on its E3-SUMO ligase activity that regulates the sex-specific SUMOylation profile of ovarian-specific genes. Our study identifies TRIM28 as a key factor in protecting the adult ovary from the testicular pathway.

developmental biology↗

bioRxiv2019

Protein Level Variability Determines Phenotypic Heterogeneity in Proteotoxic Stress Response

Cell-to-cell variability in stress response is a bottleneck for the construction of accurate and predictive models that could guide clinical diagnosis and treatment of diseases as for instance cancers. Indeed such phenotypic heterogeneity can lead to fractional killing and persistence of a subpopulation of cells resistant to a given treatment. The heat shock response network plays a major role in protecting the proteome against several types of injuries. We combine high-throughput measurements and mathematical modeling to unveil the molecular origin of the phenotypic variability in the heat shock response network. Although the mean response coincides with known biochemical measurements, we found a surprisingly broad diversity in single cell dynamics with a continuum of response amplitudes and temporal shapes for several stimuli strengths. We theoretically predict that the broad phenotypic heterogeneity is due to network ultrasensitivity together with variations in the expression level of chaperons controlled by heat shock factor 1. We experimentally confirm this prediction by mapping the response amplitude to concentrations chaperons and heat shock factor 1 expression level.

systems biology↗

bioRxiv2018

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase {eta} contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.

cancer biology↗