期刊
ACS CHEMICAL BIOLOGY
卷 12, 期 9, 页码 2260-2263出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.7b00521
关键词
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资金
- National Institutes of Health [T32 GM8403-23, RO1 GM056834, RO1 CA74305]
Nuclear human uracil-DNA glycosylase (hUNG2) initiates base excision repair (BER) of genornic uracils generated through misincorporation of dUMP or through deamination of cytosines. Like many human DNA glycosylases, hUNG2 contains an unstructured N-terminal domain that encodes a nuclear localization signal, protein binding motifs, and sites for post-translational modifications. Although the N-terminal domain has minimal effects on DNA binding and uracil excision kinetics, we report that this domain enhances the ability of hUNG2 to translocate on DNA chains as compared to the catalytic domain alone. The enhancement is most pronounced when physiological ion concentrations and rnacromolecular crowding agents are used. These data suggest that crowded conditions in the human cell nucleus promote the interaction of the N-terminus with duplex DNA during translocation. The increased contact time with the DNA chain likely contributes to the ability of hUNG2 to locate densely spaced uracils that arise during somatic hypermutation and during fluoropyrimidine chemotherapy.
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