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Abstract
Uracil-DNA glycosylase (UDG) is one of the most important base excision repair (BER) enzymes involved in the repair of uracil-induced DNA lesion by removing uracil from the damaged DNA. Uracil in DNA may occur due to cytosine deamination or deoxy uridine monophosphate (dUMP) residue misincorporation during DNA synthesis. Medical evidences show that an abnormal expression of UDG is related to different types of cancer, including colorectal cancer, lung cancer, and liver cancer. Therefore, the research of UDG is crucial in cancer treatment and prevention as well as other clinical activities. Here we applied multiple computational methods to study UDG in several perspectives: Understanding the stability of the UDG enzyme in different pH conditions; studying the differences in charge distribution between the pocket side and non-pocket side of UDG; analyzing the field line distribution at the interfacial area between UDG and DNA; and performing electrostatic binding force analyses of the special region of UDG (pocket area) and the target DNA base (uracil) as well as investigating the charged residues on the UDG binding pocket and binding interface. Our results show that the whole UDG binding interface, and not the UDG binding pocket area alone, provides the binding attractive force to the damaged DNA at the uracil base.
Highlights
DNA damage happens with a rate of ten thousand to one million molecular lesions per cell every day (Alberts, 2008)
The uracil base flips out to the Uracil-DNA glycosylase (UDG) binding pocket so that UDG hydrolyzes the uracil from DNA
We found that compared to the cytosine base, the uracil base generally forms stronger attractive forces to UDG (Figure 8B) and stronger repulsive forces to the UDG pocket (Figure 8C), but the differences between the force strengths generated by uracil and cytosine are insignificant
Summary
DNA damage happens with a rate of ten thousand to one million molecular lesions per cell every day (Alberts, 2008) It may be caused by endogenous damages, such as reactive oxygen species (ROS), and exogenous damages, such as X-ray and UV radiation, plant toxins, and viruses (Jackson and Bartek, 2009). DNA repair is an important mechanism that includes base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) (Wood et al, 2001; Helleday et al, 2008). Among these mechanisms, BER is the process of removing damaged bases which may cause mutations by mispairing or even result in DNA damage (Liu et al, 2007)
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