Genome complexity: enzyme controls on histones (Introduction)

by David Turell , Sunday, December 25, 2022, 17:12 (489 days ago) @ David Turell

Just discovered:

https://www.sciencedaily.com/releases/2022/12/221222123123.htm

'After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome -- a rare genetic, neurocognitive disorder.

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"The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks -- a process called methylation, which adds chemical tags to a part of histones called H3K23 -- the DNA becomes damaged and the cells grow poorly.

"In a follow up study published in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species.

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"Taverna, recent Ph.D. graduate David Vinson and Srinivasan Yegnasubramanian, M.D., Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led a new study to search for the mammalian enzymes that add the chemical tags to H3K23.

"After screening many enzymes that write methylation, Vinson found just one pair of enzymes, EHMT1/GLP and EHMT2/G9a, which placed chemical tags on the H3K23 histone location.

"When the researchers used drug inhibitors and genetic mutations directed against the enzyme pair in human brain cells (neurons) grown in the laboratory, the ability of the enzymes to place methylation tags on the H3K23 histone location reduced significantly.

"'With this initial precedent established in human neuronal cells, the door is now wide open to study the role of these enzymes and the H3K23 modification in numerous contexts of health and disease, including human cancer," says Yegnasubramanian.

"Now that the researchers know that EHMT1/GLP and EHMT2/G9a place chemical tags on the H3K23 histone location, they are aiming to understand the precise mechanism of how they do so and develop drugs that target this activity."

Comment: these enzymes offer tight control over DNA errors when wound on histones. I'll remind, enzymes are giant very specified molecules. To work they must be designed all at once, and never could evolve stepwise.