Journal Club: Cell Biology, Stem Cell Biology, Cell Biology, and Respiratory Pathology

CELL BIOLOGY: Early telomerase inactivation accelerates aging independently of telomere length. Xie, Z., et al. (Blackburn, E.H.) Cell. 2015. 160(5):928-939.

Telomeres, repetitive DNA sequences at the end of chromosomes, are essential for DNA protection. Loss of the telomerase enzyme leads to gradual shortening of telomeres—after each cell division—leading, eventually, to a DNA damage response and loss of the ability to keep proliferating.

Previous research has only described the consequences of telomerase inactivity after many cell divisions. This paper from the Blackburn lab, however, presents evidence that deletion of telomerase leads to negative effects long before telomeres substantially shorten.

Working with budding yeast, the authors found an increase in transient DNA damage responses in yeast lacking telomerase and faster aging. This effect was not due to increased reactive oxygen species or deprotected telomeres. It could be rescued by increased dNTP availability.

STEM CELL BIOLOGY: CDK inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation.  Huskey, N.E. et al. (Goga, A.). Stem Cell Reports. 2015. Epub ahead of print. 

Tumors arising from differentiated tissues, such as breast cancer or lung cancer, often show loss of some of the characteristic features of the starting tissue. In contrast, tumors arising from embryonic stem cells (ESCs), called teratomas, show increased differentiation, at times in a chaotic mix--a tooth-like region here, a gut-like region there.

ESCs also have a slightly different cell cycle progression than differentiated cells, with accelerated expression of certain regulatory proteins, including CDK1. Here, the authors investigated the effect of CDK1 inhibition on ESCs.

They found that this inhibition led to a DNA damage response and activation of certain p53 target genes. Furthermore, they found that CDK1 inhibition could both prevent the onset of ESC-derived tumors and lead to death of already formed tumors.

CELL BIOLOGY: Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. Osman, C. et al. (Walter, P.). PNAS. 2015. 112(9):E947-56.

Since a bacteria became symbiotic with an early eukaryote, giving rise to what we now call the mitochondrion, much of the original bacterial genome has been lost, and most of those that remain have now migrated over to the nuclear genome. A handful, however, remain where they began, as mitochondrial DNA (mtDNA).

mtDNA is present in many copies in each cell and are distributed throughout the cell’s mitochondria. In this paper, Osman and colleagues used a new system for imaging mtDNA dynamics to gain new insights.

The researchers were surprised to find that cells unable to combine and split mitochondria normally nevertheless showed a normal distribution of mtDNA and passed it along successfully during cell division. The mtDNA in these cells was not wholly healthy, however, showing harmful structural changes near the origins of replication.

RESPIRATORY PATHOLOGY: Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Yuan, S. et al. (Fahy, J.V.). Sci Transl Med. 2015. 7(276):276ra27. 

Although advances in care over the past generation have substantially increased the life expectancies of people with cystic fibrosis, it remains a dangerous and incurable disease. It is caused by mutations in the CFTR receptor, leading primarily to lung and pancreatic problems.

Previous research has found that the airway mucus in CF patients is more elastic than normal, but how this comes to be was unclear. Here, the researchers provide evidence that this difference can be explained by inflammation-associated oxidation causing increased mucin cross-linking.

The researchers found that high levels of reactive oxygen species in CF correlate with increased disulfide cross-linking, and mucus from healthy individuals exposed to increased oxidizing stimuli showed similar changes. In addition, the authors found that a thiol-carbohydrate was more effective at decreasing mucus elasticity than the thiol-amino drugs such as N-acetylcysteine.