Woodhouse-Sakati syndrome – From a new premature aging disorder towards aging mechanisms
Final Report Abstract
In total, my project revealed that the monogenic disorder Woodhouse-Sakati syndrome can be classified as a new premature aging disease. The disease is caused by mutations in the gene DCAF17, encoding a protein that has been suggested to function in the CUL4A-DDB1 E3 ubiquitin ligase complex. However, there is no mechanistic understanding of the DCAF17-containing protein complex and thus, the underlying pathogenesis of Woodhouse-Sakati syndrome remains a mystery. In this study, we describe the first Scandinavian patients suffering from Woodhouse-Sakati syndrome. The patients display several features of aging, which were further supported by the observation of increased cellular senescence in isolated peripheral blood mononuclear cells of the patients. Further, my data unravel novel interaction characteristics of the DDB1-DDA1-DCAF17 protein complex and how those affect the stability of the protein complex. DCAF17, itself, is recruited to the DNA damage site, and in line with this, loss of DCAF17 leads to decreased genome stability and altered DNA metabolism. In summary, our findings corroborate the role of DNA maintenance as critical for healthy aging. Future research on substrate recognition of the DCAF17-containing DDB1 E3 ubiquitin ligase complex will be necessary to fully understand the pathomechanism of the disease.
Publications
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(2017) Monogenic Diseases of DNA repair. The New England journal of medicine, 377, 1868-1876
Keijzers G, Bakula D, Scheibye-Knudsen M
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(2018) Aging and drug discovery. Aging (Albany NY),10, 3079-3088
Bakula D, Aliper AM, Mamoshina P, Petr MA, Teklu A, Baur JA, Campisi J, Ewald CY, Georgievskaya A, Gladyshev VN, Kovalchuk O, Lamming DW, Luijsterburg MS, Martín-Montalvo A, Maudsley S, Mkrtchyan GV, Moskalev A, Olshansky SJ, Ozerov IV, Pickett A, Ristow M, Zhavoronkov A, Scheibye-Knudsen M
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(2019) Latest advances in aging research and drug discovery. Aging (Albany NY), 11, 9971-9981
Bakula D, Ablasser A, Aguzzi A, Antebi A, Barzilai N, Bittner MI, Jensen MB, Calkhoven CF, Chen D, Grey ADNJ, Feige JN, Georgievskaya A, Gladyshev VN, Golato T, Gudkov AV, Hoppe T, Kaeberlein M, Katajisto P, Kennedy BK, Lal U, Martin-Villalba A, Moskalev AA, Ozerov I, Petr MA, Reason, Rubinsztein DC, Tyshkovskiy A, Vanhaelen Q, Zhavoronkov A, Scheibye-Knudsen M
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(2020) MitophAging: Mitophagy in Aging and Diseases. Front. Cell. Dev. Biol., 15;8:239
Bakula D and Scheibye-Knudsen M
