DNA Repair Mechanisms Sometimes Cause Errors That Contribute to Disorders Such as Huntington’s Disease

A team of scientists has discovered another way that DNA becomes mutated. A special repair process, called break-induced replication, is implicated in neurodegenerative diseases such as Huntington’s disease. The details are in a paper that was just published in the journal Nature Structural & Molecular Biology.

Genetic mutations can be caused by everything from ultra-violet damage to radiation. Most mutations, however, are caused by issues with the molecular machinery involved in DNA replication. Errors can occur and while most are fixed, even the fixes can potentially lead to mutations. One type of error results in the repetition of the same bases over and over. A segment that reads as CTG might end up reading as CTGCTGCTG, for example. This type of replication error can be dangerous and is connected to a number of disorders, including myotonic dystrophy, spinocerebellar ataxia, and Huntington’s disease.

Researchers from Tufts University investigated the possible causes of these dangerous repeat errors. Previous research had identified certain gene mutations in repair machinery that were connected to the errors but the actual mechanisms were unknown. The team used Baker’s yeast (Saccharomyces cerevisiae) in their study because the yeast’s genome is easy to work with. They found that sometimes the DNA replication machinery would briefly pause at the repeated sequence, often leading to a breakage. There are checkpoint and repair mechanisms in place to deal with these kinds of problems but the team observed something unusual. The repair mechanism, called break-induced replication, was taking “shortcuts” and some of the usual proteins were not involved in these specific types of repairs. This appeared to be a way for the DNA to quickly patch things up but it came at a cost—repeat errors were more likely to occur.

The team’s findings show that break-induced replication is a way to quickly repair DNA but can cause dangerous repeat errors. These errors contribute to disorders such as Huntington’s disease and other neurodegenerative diseases.

REFERENCE

Kim et al. The role of break-induced replication in large-scale expansions of (CAG)n/(CTG)n repeats. Nature Structural & Molecular Biology (2016).

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