Genome complexity: DNA repair two ways (Introduction)

by David Turell , Thursday, September 21, 2017, 17:27 (2621 days ago) @ David Turell

There is a slow and a fast repair:

http://www.salk.edu/news-release/right-way-repair-dna/

Is it better to do a task quickly and make mistakes, or to do it slowly but perfectly? When it comes to deciding how to fix breaks in DNA, cells face the same choice between two major repair pathways. The decision matters, because the wrong choice could cause even more DNA damage and lead to cancer.

Salk Institute scientists found that a tiny protein called CYREN helps cells choose the right pathway at the right time, clarifying a longstanding mystery about DNA repair.

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Double-strand breaks, the most serious injuries that happen to DNA, can be repaired by one of two pathways: a fast but error-prone process known as NHEJ (non-homologous end joining) and a slower, error-free pathway known as HR (homologous recombination). The faster pathway efficiently rejoins broken strands, but in the case of multiple breaks it can join the wrong two ends together, making things much worse for a cell. The slower pathway is error-free because it relies on having an undamaged DNA sequence to guide the repair, but this means it can only operate after a cell has copied its genetic information in order to divide. Given that, the fast pathway operates exclusively before DNA is copied, though its machinery is so efficient and prolific that scientists have wondered why it doesn’t outcompete the slower, more-exact pathway after copying, too. Scientists have long suspected that something must be holding the faster option back in those cases.

That something, the new work reveals, is a microprotein called CYREN, which inhibits the faster pathway when a DNA copy is available for the slower pathway to use. CYREN was discovered by another Salk scientist, Alan Saghatelian, as part of a 2015 effort to identify small proteins called “short ORF-encoded peptides” or SEPs, which are increasingly being found to have critical biological roles.

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The Salk team ... found that with CYREN present, no repairs occurred after the cell copies its DNA, suggesting that it does flip off the master switch, Ku. Without CYREN around, Ku’s fast pathway was active both before DNA was copied and after.

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These experiments revealed that CYREN directly attaches to Ku to inhibit the fast pathway both depending on timing (before or after DNA copying) and the type of DNA break (smooth versus jagged, for example). Its activity can even tune the ratio of fast to slow repairs.

“Our study shows that CYREN is an important regulator of DNA-repair-pathway choice,” says Karlseder, who holds the Donald and Darlene Shiley Chair at Salk.

Comment: accurate DNA repair is essential for life to continue to exist in proper forms. Dividing cells do make decisions as this research shows, safely going slow when DNA is well organized. This is obviously an automatic system which depends on the status of DNA organization. Too complex to be developed by chance.