Cells. 2022 May 25;11(11):1737. doi: 10.3390/cells11111737.

Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse

Céline Cruciani-Guglielmacci ¹, Kelly Meneyrol ¹, Jessica Denom ¹, Nadim Kassis ¹, Latif Rachdi ², Fatna Makaci ², Stéphanie Migrenne-Li ¹, Fabrice Daubigney ¹, Eleni Georgiadou ³, Raphaël G Denis ^1 2, Ana Rodriguez Sanchez-Archidona ⁴, Jean-Louis Paul ⁵, Bernard Thorens ⁴, Guy A Rutter ^3 6 7, Christophe Magnan ¹, Hervé Le Stunff ⁸, Nathalie Janel ¹

Abstract

Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/-) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/- mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/- mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis.

Keywords: autonomic nervous system; hyperhomocysteinemia; insulin secretion; type 2 diabetes.

• PMID: 35681432
• PMCID: PMC9179272
• DOI: 10.3390/cells11111737

Life Sci Alliance. 2022 Jan 11;5(4):e202101153. doi: 10.26508/lsa.202101153. Print 2022 Apr.

Chl1 helicase controls replication fork progression by regulating dNTP pools

Amandine Batté ¹, Sophie C van der Horst ¹, Mireille Tittel-Elmer ^1 2, Su Ming Sun ¹, Sushma Sharma ³, Jolanda van Leeuwen ⁴, Andrei Chabes ³, Haico van Attikum ⁵

Abstract

Eukaryotic cells have evolved a replication stress response that helps to overcome stalled/collapsed replication forks and ensure proper DNA replication. The replication checkpoint protein Mrc1 plays important roles in these processes, although its functional interactions are not fully understood. Here, we show that MRC1 negatively interacts with CHL1, which encodes the helicase protein Chl1, suggesting distinct roles for these factors during the replication stress response. Indeed, whereas Mrc1 is known to facilitate the restart of stalled replication forks, we uncovered that Chl1 controls replication fork rate under replication stress conditions. Chl1 loss leads to increased RNR1 gene expression and dNTP levels at the onset of S phase likely without activating the DNA damage response. This in turn impairs the formation of RPA-coated ssDNA and subsequent checkpoint activation. Thus, the Chl1 helicase affects RPA-dependent checkpoint activation in response to replication fork arrest by ensuring proper intracellular dNTP levels, thereby controlling replication fork progression under replication stress conditions.

• PMID: 35017203
• DOI: 10.26508/lsa.202101153