In This Issue
BIOCHEMISTRY
DNA unwinding via minichromosome maintenance
Minichromosome maintenance (MCM) proteins play an essential role in DNA unwinding and are completely conserved throughout eukaryotic and archaeal cells, underscoring their fundamental importance in DNA replication. Biochemists have characterized some of the protein motifs that affect the unwinding of DNA by MCM proteins. Elizabeth Jenkinson and James Chong studied how changes in the MCM proteins of a methanogenic archaeon affected DNA replication. The authors found that amino acid substitutions in the MCM protein affected ATP hydrolysis, DNA binding, and duplex unwinding. A single amino acid change in the N terminus or a deletion of a 72-aa sequence in the C terminus disrupted the movement of an internal helix that controls DNA binding and unwinding. Jenkinson and Chong also deleted the internal helix, which completely stopped DNA unwinding. However, this change also sped up ATP hydrolysis, showing that the wild-type MCM protein may not be working at peak efficiency. These results provide insights into MCM proteins’ helicase activity and control of the DNA binding and unwinding process. — P.D.
Theoretical model of MCM protein.
“Minichromosome maintenance helicase activity is controlled by N- and C-terminal motifs and requires the ATPase domain helix-2 insert” by Elizabeth R. Jenkinson and James P. J. Chong (see pages 7613–7618)
IMMUNOLOGY
Lack of lectins in human immune diseases
Although humans and chimpanzees share >99% protein identity, they demonstrate some glaring molecular differences that may explain the prevalence of certain diseases in humans. Dzung Nguyen et al. report one such change that occurred after the human–chimpanzee evolutionary split: the stronger proliferative response of human T cells to specific activation via the T cell receptor (TCR). Although both human and chimpanzee T cells display robust nonspecific activation, chimpanzees produce almost 100-fold fewer T cells after TCR activation by antibodies. The apparent reason for this difference is that the T cells of chimpanzees and other great apes express multiple Siglecs (sialic acid-recognizing lectins), which act as inhibitory signaling molecules, whereas human T cells express few or none. Confirming this difference, Nguyen et al. showed that clearance of Siglec-5 from chimpanzee T cells and transfection of Siglec-5 into primary human T cells can, respectively, decrease or increase TCR activation. Strikingly, T cells are the only human immune cells that lack Siglec expression. This finding may help explain the prevalence and severity of T cell-mediated diseases such as chronic hepatitis, rheumatoid arthritis, type 1 diabetes, and AIDS among humans. — N.Z.
Siglec-positive lymphocytes in humans vs. apes.
“Loss of Siglec expression on T lymphocytes during human evolution” by Dzung H. Nguyen, Nancy Hurtado-Ziola, Pascal Gagneux, and Ajit Varki (see pages 7765–7770)
NEUROSCIENCE
Single nucleotide difference in heroin abuse
μ Opioid receptors (MORs) are critical for signaling in heroin dependence. In certain populations, a single nucleotide polymorphism of the human MOR gene, OPRM1, has been linked with heroin abuse. Katarina Drakenberg et al. provide insight into the neurobiological mechanisms mediated by the OPRM1 polymorphism. In the authors’ study of a homogenous racial and ethnic population of European Caucasians, nearly 90% of the subjects who had the polymorphism used heroin. These individuals expressed the opioid neuropeptide preproenkephalin (PENK) and preprodynorphin (PDYN) mRNAs in lower levels than other heroin users and controls. PENK levels in the nucleus accumbens section of the brain, which is linked with reward and goal-oriented behavior, were found to be decreased by >40%. In this population, a discordance in the transcription of neuropeptides derived from PENK and PDYN was observed. Intracellular processing genes, such as those responsible for ubiquitination and proteasomal degradation, were also expressed in lower levels in heroin users with the OPRM1 polymorphism. These findings, linking disturbances in the opioid neuropeptide system to intracellular processing in heroin users, may provide an important step in understanding and treating human addiction disorders. — F.A.
Opioid receptor polymorphism in heroin abuse.
“μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers” by Katarina Drakenberg, Andrej Nikoshkov, Monika Cs Horváth, Pernilla Fagergren, Anna Gharibyan, Kati Saarelainen, Sadia Rahman, Ingrid Nylander, Georgy Bakalkin, Jovan Rajs, Eva Keller, and Yasmin L. Hurd (see pages 7883–7888)
PHYSIOLOGY
Growth hormone could be a key to longevity
Numerous studies have shown that long-term calorie restriction increases longevity in animals, yet the biological basis for this effect has remained elusive. A new study by Michael Bonkowski et al. points to growth hormone as a possible mediating factor in the life-extending effects of calorie restriction. Separately, both calorie restriction and mutations affecting growth hormone and/or insulin signaling have been shown to increase longevity in mice. To test whether these signaling pathways participate in the beneficial effects of calorie restriction, Bonkowski et al. examined the effects of calorie restriction in mice lacking growth hormone receptor. The researchers found that calorie restriction in normal mice increased longevity by between 18.8% (males) and 28% (females), as expected. Mice lacking growth hormone receptor showed similar longevity when allowed free access to food. However, calorie restriction failed to increase their lifespan any further. The results suggest that growth hormone signaling may be a key mediator of the life-extending effects of calorie restriction, perhaps through alterations in insulin sensitivity. The authors note that these findings point to the growth hormone and insulin signaling pathways as potential targets for developing life-extending pharmaceuticals. — M.M.
“Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction,” by Michael S. Bonkowski, Juliana S. Rocha, Michal M. Masternak, Khalid A. Al Regaiey, and Andrzej Bartke (see pages 7901–7905)
PLANT BIOLOGY
Hormone sensitivity protein in fruit ripening
In plants such as the tomato, the hormone ethylene directs fruit ripening. Previous research has shown that a reduced ethylene sensitivity leads to the nonripening phenotype of two tomato mutants, Green-ripe (Gr) and Never-ripe 2 (Nr-2), but the mechanisms by which the ethylene signal is perceived and transduced have not been fully understood. Cornelius Barry and James Giovannoni have identified an evolutionarily conserved protein that helps elucidate the ethylene response mechanism in tomato plants. The authors isolated the Gr and Nr-2 loci in the plants’ genomes and found that the mutants had identical deletions in a region of the same gene, GR. Transgenic overexpression of the GR gene recapitulated the nonripe phenotype but did not lead to whole-plant ethylene insensitivity. Because the identification of GR provides a tool to assess tissue-specific ethylene signal transduction, the authors say it may be useful for reducing the impact of ethylene on ripe fruit while maintaining normal plant vigor. — F.A.
Ripening inhibited in transgenic tomatoes.
“Ripening in the tomato Green-ripe mutant is inhibited by ectopic expression of a protein that disrupts ethylene signaling” by Cornelius S. Barry and James J. Giovannoni (see pages 7923–7928)
