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Replicating Damaged DNA

DNA polymerases assist in DNA replication by catalyzing the polymerization of deoxyribonucleotides along-side a template DNA strand. Based on sequence homology, DNA polymerases can be subdivided into seven different families, A, B, C, D, X, Y, and RT. The Y family polymerases differ from others in that they are able to use damaged DNA as a template. For example, P2 DNA polymerase IV (Dpo4) from Sulfolobus solfataricus can bypass 7,8-dihydro-8-oxodeoxyguanosine (8-oxoG), a major lesion arising from oxidative stress.

Arg332 forms a bond with 8-oxoG during replication.

In this Paper of the Week, Robert L. Eoff and colleagues looked at the means by which Dpo4 is able to bypass this lesion with high fidelity, thus preventing mutation. Previous crystal structures had indicated that Arg³³² might play a role in stabilizing the 8-oxoG template base, allowing insertion of dCTP in the complementary strand. The authors investigated the role of this amino acid in nucleotide selection using site-directed mutagenesis to alter different chemical aspects of the Arg³³² side chain. Transient state kinetic and LC-MS/MS analyses were then combined with x-ray crystallographic studies to compare mutant-catalyzed bypass of 8-oxoG with wild type Dpo4. Their results confirmed that a bond between Arg³³² and 8-oxoG plays a role in determining the fidelity and efficiency of the Dpo4-catalyzed bypass.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 19831-19843

Singar1 Promotes Singular Axons

Neurons, or nerve cells, are typically composed of a soma (cell body), a dendritic tree, and an axon. Most nerve cells develop by first forming several minor processes, one of which then rapidly elongates to acquire axonal characteristics, whereas the others become dendrites. Although this polarity is essential for the basic functions of the neuron, the mechanisms that ensure generation and maintenance of a single axon remain poorly understood. Both extracellular cues and intrinsic cellular signals are known to be important for axonal preference.

Suppression of singar expression induces formation of surplus axons.

In this Paper of the Week, Tatsuya Mori and colleagues utilized a proteomic approach to identify a novel protein called singar1 that is important in the formation of axons. They show that singar1 expression is up-regulated during polarization of cultured hippocampal neurons and that overexpression of singar1 suppresses the formation of surplus axons. Conversely, a reduction in singar1 expression by RNAi leads to an increase in the population of neurons bearing surplus axons. These data suggest that singar1 functions to suppress the formation of surplus axons.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 19884-19893

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