Posted in | Microscopy

Researchers Uncover DNA Damage Checkpoint Surveillance Mechanism

In current health lore, antioxidants are all the rage, as “everybody knows” that reducing the amount of “reactive oxygen species” -- cell-damaging molecules that are byproducts of cellular metabolism -- is critical to staying healthy. What everyone doesn’t know is that our bodies already have a complex set of processes built into our cells that handle these harmful byproducts of living and repair the damage they cause.



“DNA damage is the underlying pathology in many major human diseases, including cancers and neurodegenerative disorders such as Alzheimer’s and Parkinson’s, so arriving at a full understanding of the sophisticated mechanisms that cells usually employ to avoid such disastrous outcomes is important,” Yan noted.

Two biochemical pathways, known as ATM-Chk2 and ATR-Chk1, govern the cell’s response and repair of double-strand DNA breaks and other types of DNA damage or replication stress respectively. The molecular mechanisms underlying the ATR-Chk1 checkpoint activation include the uncoupling of DNA helicase and polymerase activities and DNA end resection of double-strand breaks.


In particular, Yan’s team discovered that under conditions of oxidative stress (in the presence of hydrogen peroxide) a base excision repair protein known as APE2 plays unexpected roles in the checkpoint response: single-strand DNA generation and Chk1 association. The protein was previously known to be involved in the DNA repair of oxidative damage, but not to extent revealed in the study’s findings. The distinct role of APE2 in the single-stand DNA generation in 3’ to 5’ direction is referred to as single-strand break end resection (“SSB end resection”) by the authors.

The study involved experiments performed with Xenopus laves (the African clawed frog, a species commonly used as a lab animal) egg extracts – an experimental system that Yan’s lab has developed for studying DNA repair and checkpoint mechanisms in a cell-free conditions. Xenopus is useful because it is a vertebrate (and thus quite similar to humans in cell biology), and its egg cells can be easily produced and manipulated.


The article appeared in the June 10, 2013 print edition of PNAS: The Yan laboratory at UNC Charlotte is funded in part by the University of North Carolina at Charlotte and a National Institute of General Medical Sciences/National Institutes of Health grant, number R15GM101571.

Source: Shan Yan, 704-687-8528, [email protected]


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