DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin.
DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin.
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DOT1L 通过促进染色质上的降解循环来刺激 MYC/Mondo 转录因子活性。
DOI：
10.1101/2024.02.06.579191
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Grishok,Alla
中科院分区：
文献类型：
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作者：
Sepulveda,GianP;Gushchanskaia,EkaterinaS;Mora-Martin,Alexandra;Esse,Ruben;Nikorich,Iana;Ceballos,Ainhoa;Kwan,Julian;Blum,BenjaminC;Dholiya,Prakruti;Emili,Andrew;Perissi,Valentina;Cardamone,MariaD;Grishok,Alla
原癌基因c-MYC是MYC转录因子网络调节生长和代谢的关键代表。MML-1 （Myc- and Mondo-like）是它在秀丽隐杆线虫中的同源物。c-MYC和H3赖氨酸79甲基转移酶DOT1L之间的功能和分子合作已在几种人类癌症类型中得到证实，我们早些时候发现了秀丽隐杆线虫MML-1和DOT-1.1之间的联系。在这里，我们证明了DOT1L/DOT-1.1通过确保核蛋白酶体从染色质上去除“废”转录因子，在全基因组范围内调节c-MYC/MML-1靶基因中的关键作用。此外，我们发现了以前未被识别的DOT1L蛋白水解活性，这可能促进c-MYC的周转。这种由DOT1L调控c-MYC的新机制可能会导致癌症治疗新方法的发展。
The proto-oncogene c-MYC is a key representative of the MYC transcription factor network regulating growth and metabolism. MML-1 (Myc- and Mondo-like) is its homolog in C. elegans. The functional and molecular cooperation between c-MYC and H3 lysine 79 methyltransferase DOT1L was demonstrated in several human cancer types, and we have earlier discovered the connection between C. elegans MML-1 and DOT-1.1. Here, we demonstrate the critical role of DOT1L/DOT-1.1 in regulating c-MYC/MML-1 target genes genome-wide by ensuring the removal of “spent” transcription factors from chromatin by the nuclear proteasome. Moreover, we uncover a previously unrecognized proteolytic activity of DOT1L, which may facilitate c-MYC turnover. This new mechanism of c-MYC regulation by DOT1L may lead to the development of new approaches for cancer treatment.