How DNA heals itself? Scientists discover an ancient multi-functional repair factor

If a fracture or a broken tendon occurs, people will seek treatment immediately. In fact, the most vulnerable part of us is DNA, which breaks at an alarming rate – a single cell is expected to break 10,000 times a day, but usually withno adverse consequences. THERE ARE MANY CAUSES OF DNA DAMAGE, CHEMICAL, PHYSICAL MUTATION DAMAGE, OR JUST DAILY WEAR AND TEAR OR AGING, BUT THERE ARE USUALLY THOUSANDS OF PROTEINS BEHIND IT THAT ACT AS A FIX FOR DNA AT ALL TIMES.

Proteins that carry out this task are common in all species, and in fact, without proteins committed to DNA repair, humans and bacteria, life cannot be sustained.

A new study by Anjana Rao, a researcher at the La Jolla Institute of Immunology (LJI), and her co-authors reveals the many previously undiscovered activities of a DNA repair factor that has evolved highly conservatively. Rao is a fellow of the American Academy of Sciences and has achieved important results in the field of immunology and epigenetics. The study was published on December 2nd in molecular cell, a leading academic journal.

How DNA heals itself? Scientists discover an ancient multi-functional repair factor

The paper reports that lymphocytes in genetically engineered mice that lack HMCES proteins cannot recombine DNA and thus cannot produce the daily required immunoglobulin G or A (IgG or IgA). The discovery means HMCES, which has previously been reported to fix DNA single-chain gaps, is also involved in so-called end-replacement connections. It is worth noting that this is a strategy used by mammalian cells to reconnect severe cuts on the double helix chains.

This latest discovery and other recent paper reports suggest that this long-neglected DNA repair factor, which dates back at least 3 billion years to a long time, has performed multiple tasks to protect cells from genomic instability.

“When normal B lymphocytes are activated, a fragment of DNA encoded in the IgM antibody is cut out and then reconnected (DNA recombination) to produce other more effective antibodies. “Immunologists will be called class switch recombination (CSR). “For decades, immune cells have been known to use this gene editing to produce powerful antibodies,” said lead author Vipul Shukla. We now find that HMCES not only recognizes these double-stranded breaks, but also helps reconnect them. “

The study was carried out years ago by Rao’s lab. The latest research in the lab focuses on the DNA-modified epigenetic regulator TET protein, a TET chemically modified protein that binds to HMCES. That’s why they became interested in HMCES.

They hypothesized that HMCES proteins and TET proteins may have been involved in similar biological tasks. As a result, they “knocked out” the HMCES gene in experimental mice, predicting blood cell defects and even cancer in animals, often associated with TET mutations.

Surprisingly, their predictions did not happen. The paper notes that the blood cells of HMCES-defective mice are normal and that DNA modifications that rely on TET are almost completely damaged.

However, the fact that normally activated B lymphocytes expressed large amounts of RNA encoded in HMCES prompted the team to compare the immune response of B lymphocytes with HMCES defects to normal adult B lymphocytes. After antigen stimulation, normal B cells can expectto “switch” their antibody library from IgM to IgG antibodies. In contrast, lymphocytes in HMCES-defective mice were less efficient at making IgG antibodies. The team believes this may be that, without HMCES, the CSR mechanism that “recombinations” DNA to convert IgM into other IgG antigens is less effective.

“In this study, we used lymphocytes as a model system to identify THE new role of HMCES in the little-known DNA double-stranded fracture repair pathway. Shukla said, “This pathway not only works in immune cells, but the double-stranded fracture repair we describe here may occur in the DNA damage response of any cell in the body.” “

The new study shows that HMCES is versatile enough to perform completely different tasks to deal with DNA damage as needed. For example, the paper’s co-authors, Dr. Levon Halabelian and Dr. Cheryl Arrowsmith of the University of Toronto, identified the 3-D structure of HMCES and several types of “broken” DNA strands in a previous study. Demonstrates how HMCES plays multiple roles in cells.

In this latest study, their structure also reveals how HMCES coordinates the end connections of B cells. In addition, some studies have mentioned that in some cases, HMCES can protect damaged single-stranded DNA from further degradation.

In addition, HMCES is the only human protein that contains the bacterial protein YedK conservative domain, which is involved in the repair of E. coli DNA. Dr. L. Aravind, one of the authors of the paper’s newsletter, said the findings suggest that proteins like HMCES have the ability to recognize and respond reasonably to various signals from genomic “crisis” during evolution.

“Many DNA repair proteins have ancient origins. Aravind said HMCES’s findings added new members to such repairs.

Shukla also said, “Nature has clearly found a way to use this vital protein to promote the health of living things.” “

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