Enzyme tolerates mistakes in DNA
DNA is littered with “mistakes” — bases damaged by normal cellular processes or by an outside insult. These mistakes can signal for the cell to self-destruct. To survive, a cell may need to bypass such damage during replication.
The bacterium Sulfolobus solfataricus produces an enzyme, called DNA polymerase IV (Dpo4), capable of bypassing 8-oxo-G, a major DNA lesion caused by oxidative damage, with high fidelity and efficiency.
To determine how mutations in Dpo4 might affect its bypass ability, F. Peter Guengerich, Ph.D., and colleagues created mutant enzymes with variations in the amino acid residue at position 332 and characterized their activity. Their results, published as a “Paper of the Week” in the July 6 Journal of Biological Chemistry, demonstrate the importance of the bonding between the amino acid 332 (arginine) and the damaged DNA base in determining the fidelity and efficiency of the enzyme's bypass mechanism. Understanding such processes may aid in understanding carcinogenesis and aging, which result, in part, from DNA damage.
— Melissa Marino
Bone connectors hinge on TGF-beta
Osteoarthritis — degenerative joint disease — causes pain for more than a third of adults in industrialized countries. Anna Spagnoli, M.D., and colleagues are probing how joints develop with the idea that understanding the molecular mechanisms involved will suggest novel therapeutic approaches for diseases like osteoarthritis.
The investigators report in the June 18 Journal of Cell Biology that transforming growth factor-beta (TGF-beta) signaling is essential for joint formation. The team studied joints in mice with a conditional knockout of the type II TGF-beta receptor in limb buds and a subset of other mesenchyme tissues. The mice had missing finger joints — similar to a human syndrome called symphalangism — and other limb and midline skeletal defects. The investigators determined that the type II TGF-beta receptor is normally highly expressed in developing joints and found that its signaling regulates other genes with roles in joint development. The findings suggest that TGF-beta signaling initiates and modulates joint formation.
— Leigh MacMillan
Hedgehog in the brain
Holoprosencephaly, a condition in which the brain's hemispheres fail to completely separate into distinct halves, has been linked to aberrant Sonic hedgehog (Shh) signaling. However, the mechanisms involved remain unclear.
Previously, Chin Chiang, Ph.D., and colleagues demonstrated that Shh lacking its normal cholesterol modification (ShhN) spreads far from its site of synthesis to cause abnormal development of the digits. In the June 15 Human Molecular Genetics, Chiang and Xi Huang show that the ectopic ShhN signaling may also interfere with the proper separation of the brain's hemispheres by altering Bmp, Wnt and Fgf8 signaling. Mice with ectopic ShhN expression exhibited partial division of the cerebral hemispheres, hydrocephalus and cleft palate — features seen in a mild form of human holoprosencephaly.
The results reveal a novel mechanism of Shh action in brain development and suggest that, in contrast with the current notion that inadequate Shh signaling causes holoprosencephaly, genetic variations that cause ectopic or excessive Shh signaling may also underlie some milder forms of holoprosencephaly.
— Melissa Marino
Lizard spit in lieu of insulin?
For patients with type 2 diabetes, insulin is the treatment of choice when diet, exercise and oral antidiabetic agents fail to control blood glucose levels. But insulin therapy is often accompanied by undesirable weight gain and hypoglycemia. Exenatide, originally discovered in the saliva of the Gila monster, is the first of a new class of antidiabetic drugs that mimic the actions of glucagon-like peptide-1. Exenatide also is associated with a reduction in body weight.
Stephen Davis, M.D., and colleagues conducted an exploratory, multi-center trial to test exenatide as a substitute for insulin in patients being treated with insulin in combination with oral antidiabetic agents. They report in Diabetes Care that although most of the exenatide-treated patients lost weight, a third of them experienced a deterioration in glucose control. Exenatide was less likely to benefit patients with longer disease duration or who were taking higher doses of insulin.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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