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2. Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function

Author

Majtan, Tomas, Olsen, Thomas, Sokolova, Jitka, Krijt, Jakub, Křížková, Michaela, Ida, Tomoaki, Ditrói, Tamás, Hansikova, Hana, Vit, Ondrej, Petrak, Jiri, Kuchař, Ladislav, Kruger, Warren D., Nagy, Péter, Akaike, Takaaki, and Kožich, Viktor

Published
2024
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3. CRY1‐CBS binding regulates circadian clock function and metabolism

Author

Cal‐Kayitmazbatir, Sibel, Kulkoyluoglu‐Cotul, Eylem, Growe, Jacqueline, Selby, Christopher P, Rhoades, Seth D, Malik, Dania, Oner, Hasimcan, Asimgil, Hande, Francey, Lauren J, Sancar, Aziz, Kruger, Warren D, Hogenesch, John B, Weljie, Aalim, Anafi, Ron C, and Kavakli, Ibrahim Halil

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Sleep Research, 1.1 Normal biological development and functioning, Underpinning research, Metabolic and endocrine, ARNTL Transcription Factors, Amino Acid Sequence, Animals, CLOCK Proteins, Circadian Clocks, Circadian Rhythm, Cryptochromes, Cystathionine beta-Synthase, E-Box Elements, Female, HEK293 Cells, Humans, Male, Metabolic Networks and Pathways, Metabolome, Mice, Mice, Knockout, Mutation, Period Circadian Proteins, Protein Binding, Protein Processing, Post-Translational, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, circadian rhythms, cryptochrome, intrinsically disordered protein, CON NMR, delayed sleep phase disorder, Transcription, Genetic, Protein Domains
Abstract

Circadian rhythms are generated by interlocked transcription-translation feedback loops that establish cell-autonomous biological timing of ∼24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1Δ11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the Δ11 variant alters an intrinsically disordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. Moreover, PHR-tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR-tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.

Published
2021

4. An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract

Author

Skvorak, Kristen, Mitchell, Vesna, Teadt, Leann, Franklin, Kierra A., Lee, Hyung-Ok, Kruse, Nikki, Huitt-Roehl, Callie, Hang, Julie, Du, Faye, Galanie, Stephanie, Guan, Steven, Aijaz, Hera, Zhang, Nianliu, Rajkovic, Gabriel, Kruger, Warren D., Ismaili, Moulay Hicham Alaoui, Huisman, Gjalt, McCluskie, Kerryn, and Silverman, Adam P.

Published
2023
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7. Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-Ok, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Published
2021
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8. Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-Ok, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Published
2021
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9. Supplemental Table 4 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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10. Supplemental Table 3 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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11. Supplemental Tables 5-7 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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12. Supplemental Table 1 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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13. Data from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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14. Supplementary Figures from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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15. Key Resources Table from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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16. Supplemental Table 8 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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17. Supplemental Table 2 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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23. Supplementary Figures 1-3, Table 1 from Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Author

Kadariya, Yuwaraj, primary, Yin, Bu, primary, Tang, Baiqing, primary, Shinton, Susan A., primary, Quinlivan, Eoin P., primary, Hua, Xiang, primary, Klein-Szanto, Andres, primary, Al-Saleem, Tahseen I., primary, Bassing, Craig H., primary, Hardy, Richard R., primary, and Kruger, Warren D., primary

Published
2023
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24. Supplementary Figure Legends 1-3 from Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma

Author

Kadariya, Yuwaraj, primary, Yin, Bu, primary, Tang, Baiqing, primary, Shinton, Susan A., primary, Quinlivan, Eoin P., primary, Hua, Xiang, primary, Klein-Szanto, Andres, primary, Al-Saleem, Tahseen I., primary, Bassing, Craig H., primary, Hardy, Richard R., primary, and Kruger, Warren D., primary

Published
2023
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28. Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice.

Author

Gupta, Sapna, Lee, Hyung-Ok, Wang, Liqun, and Kruger, Warren D.

Subjects
PROTEASOME inhibitors, HEAT shock proteins, CYSTATHIONINE, LIVER proteins, MOLECULAR chaperones, INBORN errors of metabolism, PROTEASE inhibitors
Abstract

Classic homocystinuria is an inborn error of metabolism caused mainly by missense mutations leading to misfolded and/or unstable human cystathionine β-synthase (CBS) protein, causing the accumulation of excess total homocysteine (tHcy) in tissues. Previously, it has been shown that certain missense containing human CBS proteins can be functionally rescued in mouse models of CBS deficiency by treatment with proteasome inhibitors. The rescue by proteasome inhibitors is thought to work both by inhibiting the degradation of misfolded CBS protein and by inducing the levels of heat-shock chaperone proteins in the liver. Here we examine the effectiveness of two FDA approved protease inhibitors, carfilzomib and bortezomib, on various transgenic mouse models of human CBS deficiency. Our results show that although both drugs are effective in inducing the liver chaperone proteins Hsp70 and Hsp27, and are effective in inhibiting proteasome function, bortezomib was somewhat more robust in restoring the mutant CBS function. Moreover, there was no significant correlation between proteasome inhibition and CBS activity, suggesting that some of bortezomib's effects are via other mechanisms. We also test the use of low-doses of bortezomib and carfilzomib on various mouse models for extended periods of time and find that while low-doses are less toxic, they are also less effective at restoring CBS function. Overall, these results show that while restoration of mutant CBS function is possible with proteasome inhibitors, the exact mechanism is complicated and it will likely be too toxic for long-term patient treatment. [ABSTRACT FROM AUTHOR]

Published
2023
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30. Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, Cukierman, Edna, Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, and Cukierman, Edna

Abstract

© 2020 American Association for Cancer Research. Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

Published
2022

31. Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts

Author

Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Chang, Kai Ti, Jezek, Jan, Campbell, Alicia N., Stieg, David C., Kiss, Zachary A., Kemper, Kevin, Jiang, Ping, Lee, Hyung Ok, Kruger, Warren D., van Hasselt, Peter M., Strich, Randy, Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Chang, Kai Ti, Jezek, Jan, Campbell, Alicia N., Stieg, David C., Kiss, Zachary A., Kemper, Kevin, Jiang, Ping, Lee, Hyung Ok, Kruger, Warren D., van Hasselt, Peter M., and Strich, Randy

Published
2022

40. Recent therapeutic approaches to cystathionine beta‐synthase‐deficient homocystinuria.

Author

Majtan, Tomas, Kožich, Viktor, and Kruger, Warren D.

Subjects
AMINO acid metabolism disorders, CYSTATHIONINE, THERAPEUTICS, METHIONINE metabolism
Abstract

Cystathionine beta‐synthase (CBS)‐deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non‐responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Additional file 25 of Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-O K, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Abstract

Additional file 25. Review history.

Published
2021
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48. Additional file 1 of Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

Author

Padmanabhan, Nisha, Kyon, Huang Kie, Boot, Arnoud, Lim, Kevin, Srivastava, Supriya, Chen, Shuwen, Wu, Zhiyuan, Lee, Hyung-O K, Mukundan, Vineeth T., Chan, Charlene, Chan, Yarn Kit, Xuewen, Ong, Pitt, Jason J., Isa, Zul Fazreen Adam, Xing, Manjie, Lee, Ming Hui, Tan, Angie Lay Keng, Ting, Shamaine Ho Wei, Luftig, Micah A., Kappei, Dennis, Kruger, Warren D., Bian, Jinsong, Ho, Ying Swan, Teh, Ming, Rozen, Steve George, and Tan, Patrick

Abstract

Additional file 1. Supplementary figures.

Published
2021
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49. CRY1-CBS binding regulates circadian clock function and metabolism

Author

Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Materials Science and Engineering, Kayıtmazbatır, Sibel Çal; Çotul, Eylem Külköyluoğlu; Öner, Haşimcan; Asımgil, Hande; Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Growe, Jacqueline; Selby, Christopher P.; Rhoades, Seth D.; Malik, Dania; Francey, Lauren J.; Sancar, Aziz; Kruger, Warren D.; Hogenesch, John B.; Weljie, Aalim; Anafi, Ron C., Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Materials Science and Engineering, Kayıtmazbatır, Sibel Çal; Çotul, Eylem Külköyluoğlu; Öner, Haşimcan; Asımgil, Hande; Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), and Growe, Jacqueline; Selby, Christopher P.; Rhoades, Seth D.; Malik, Dania; Francey, Lauren J.; Sancar, Aziz; Kruger, Warren D.; Hogenesch, John B.; Weljie, Aalim; Anafi, Ron C.

Abstract

Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here, we report that cystathionine beta-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein cryptochrome 1 (CRY1). In cells, CBS augments CRY1-mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic Cbs(Zn/Zn) mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1(-/-) mice show reduced CBS activity that normalizes after the addition of exogenous wild-type (WT) CRY1. Metabolomic analysis of WT, Cbs(Zn/Zn), Cry1(-/-), and Cry2(-/-) samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1-induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.

Published
2021

50. CRY1-CBS binding regulates circadian clock function and metabolism

Author

Kayıtmazbatır, Sibel Çal; Çotul, Eylem Külköyluoğlu; Öner, Haşimcan; Asımgil, Hande; Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Growe, Jacqueline; Selby, Christopher P.; Rhoades, Seth D.; Malik, Dania; Francey, Lauren J.; Sancar, Aziz; Kruger, Warren D.; Hogenesch, John B.; Weljie, Aalim; Anafi, Ron C., Graduate School of Sciences and Engineering; College of Engineering, Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Materials Science and Engineering, Kayıtmazbatır, Sibel Çal; Çotul, Eylem Külköyluoğlu; Öner, Haşimcan; Asımgil, Hande; Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Growe, Jacqueline; Selby, Christopher P.; Rhoades, Seth D.; Malik, Dania; Francey, Lauren J.; Sancar, Aziz; Kruger, Warren D.; Hogenesch, John B.; Weljie, Aalim; Anafi, Ron C., Graduate School of Sciences and Engineering; College of Engineering, and Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Materials Science and Engineering

Abstract

Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here, we report that cystathionine beta-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein cryptochrome 1 (CRY1). In cells, CBS augments CRY1-mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic Cbs(Zn/Zn) mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1(-/-) mice show reduced CBS activity that normalizes after the addition of exogenous wild-type (WT) CRY1. Metabolomic analysis of WT, Cbs(Zn/Zn), Cry1(-/-), and Cry2(-/-) samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1-induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control., İstanbul Development Agency; Defense Advanced Research Projects Agency; National Institute of Neurological Disorders and Stroke; Scientific and Technological Research Council of Turkey (TÜBİTAK) BIDEB 2214-A Scholarship

Published
2021

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