NM23/Nucleoside Diphosphate Kinases (NDKs) are involved in regulating tumorigenesis, metastasis, and cellular development in eukaryotes, and in the prevention of mutations in bacteria. For several decades, NDKs were known only as catalysts of nonspecific phosphoryl transfer between nucleoside di-and triphosphates; this activity, however, did not explain their cellular behaviour. Recently, our laboratory has identified several members of the NM23/NDK family as nucleic acid enzymes that function in transcription and DNA repair. The present proposal will examine the biochemical mechanisms of the DNA repair activities of human and E. coil NDKs, and some of their biological functions.
Aim 1 is to study the DNA repair mechanisms of E. coil NDK that we have shown to remove the inappropriate base uracil from DNA, and to study the relevance of this repair activity to mutational avoidance and to the NDP kinase reaction in E. coil in vitro and in vivo.
Aim 2 is to establish whether human NM23/NDKs are also antimutators that can recognize and repair damaged or inappropriate bases in DNA, and to study their role in a related process that excises and repairs undamaged DNA bases.
Aim 3 is to carry out structural analyses of E. coil and human NM23/NDK interactions with DNA, in order to complement and refine the biochemical studies. The significance of the proposed works will be: (1) to show that this important family of conserved enzymes whose biological functions have been previously unknown, are, in fact, major participants in DNA repair processes and pathways; (2) to promote understanding of the role of NM23 proteins in malignancy as enzymes repairing mutations in DNA; (3) to define therapeutic targets in cancer and other human diseases.
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