Genome complexity: a new DNA repair mechanism found (Introduction)

by David Turell , Wednesday, July 18, 2018, 20:13 (2320 days ago) @ David Turell

It has several moving parts to bring ends together:

https://medicalxpress.com/news/2018-07-scientists-uncover-dna-shield-crucial.html

"Scientists have made a major discovery about how cells repair broken strands of DNA that could have huge implications for the treatment of cancer.

Their study, published in Nature today, uncovered a brand new protein complex in cells that shields broken DNA ends and controls the way in which it is repaired.

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"The newly named 'Shieldin' complex was also found to be important for generating the right type of antibodies during an immune response, and mutations could lead to immune-related disorders.

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"In healthy cells, the complex was found to attach to the ends of broken DNA so that the 'blunt ends' of the DNA have to be stuck back together directly—a quicker, messier way of repairing DNA that can sometimes be necessary for making antibodies during immune responses.
When the researchers introduced mutations into the Shieldin complex—which stop it from forming and protecting broken DNA ends—cells are free to repair DNA via a different method, and this means PARP inhibitors are no longer effective.

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"'Our study reveals for the first time a complex that is crucial for DNA repair."

Abstract: https://www.nature.com/articles/s41586-018-0340-7

"53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini1,2. This function of 53BP1 requires interactions with PTIP3 and RIF14,5,6,7,8,9, the latter of which recruits REV7 (also known as MAD2L2) to break sites10,11. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action. In one model the 53BP1 complex strengthens the nucleosomal barrier to end-resection nucleases12,13, and in the other 53BP1 recruits effector proteins with end-protection activity. Here we identify a 53BP1 effector complex, shieldin, that includes C20orf196 (also known as SHLD1), FAM35A (SHLD2), CTC-534A2.2 (SHLD3) and REV7. Shieldin localizes to double-strand-break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 and POT1. Loss of shieldin impairs non-homologous end-joining, leads to defective immunoglobulin class switching and causes hyper-resection. Mutations in genes that encode shieldin subunits also cause resistance to poly(ADP-ribose) polymerase inhibition in BRCA1-deficient cells and tumours, owing to restoration of homologous recombination. Finally, we show that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair."

Comment: Sorry there is no diagram. This is a very complex system of various proteins which had to be designed when DNA was designed. DNA repair is crucial for the survival of life. That there is more than one system indicates how important repair is.