Biology : Skin barrier formation and caspase-14



A protein known as caspase-14 has been identified as the enzyme involved in the protection of the skin against UVB damage and water loss, according to a study.
The involvement of caspase-family members in programmed cell death and inflammation is well understood but, a function for caspase-14 had previously not been identified. Using caspase-14 knockout mice, Wim Declercq and colleagues show that caspase-14 is responsible for the initial processing of profillagrin to fillagrin. Fillagrin is responsible for aggregating keratin and other proteins in the upper layers of the epidermis to form the stratum corneum – a layer of flattened dead-cell remnants that creates a protective barrier for the skin. The controlled processing of profillagrin to produce fillagrin ultimately maintains the integrity of the epidermis. In mice lacking caspase-14, their skin exhibits a defective stratum corneum and is more sensitive to water loss and UVB photodamage.
The identification of caspase-14 and its role in skin-barrier formation opens avenues for the pharmaceutical manipulation of this process to prevent the damage induced by UVB, the primary agent responsible for sunburn and skin ageing.
Author contact:
Wim Declercq (Ghent University, Belgium)
Tel: +32 9 33 13 660; E-mail: wim.declercq@dmbr.ugent.be


...And Control of all fates
Cell Biology investigates how pluripotency, the ability of a stem cell to differentiate into every cell type of the adult organism, is regulated.
Understanding how stem cells maintain their pluripotent state has involved the characterisation of a multitude of transcription factors – the proteins that determine whether a specific gene is expressed or not. Pluripotency in embryonic stem cells was thought to be controlled primarily by the transcription factors Oct3/4 and Sox2, as these proteins were believed to activate Oct-Sox enhancers – regulatory regions that determine the expression of pluripotent stem cell-specific genes. Shinji Masui and colleagues used mutant mice lacking the Sox2 gene to show that although Sox2 is needed for stem cell pluripotency, it is not required for the enhancers to function and in fact governs the expression of Oct3/4. The authors went on to show that this regulation is indirect, as Sox2 controls the expression of a number of transcription factors that in turn regulate Oct3/4 expression.
This study illustrates the precise regulation of pluripotency by key proteins, and reorders the hierarchy of these factors with Sox2 as the master regulator — another small step towards a complete understanding of stem cell biology.
Author contact:
Shinji Masui (International Medical Centre of Japan, Tokyo, Japan)
Tel: +81 3 3202 7181; E-mail: masui@ri.imcj.go.jp

The dual role of BRCA2 in DNA repair
The dual role of the gene BRCA2 in DNA repair is described in two independent studies. The studies from Stephen West’s and Luca Pellegrini’s groups shed light on the role of the gene, mutations of which result in predisposition to breast cancer and other malignancies.
The protein encoded by BRCA2 is involved in homologous recombination, a process whereby damaged DNA is repaired using an intact copy of DNA as a template. This process also includes the protein RAD51, which interacts directly with two different regions of BRCA2, called BRC and TR2. The BRC region had been previously suggested to be involved in terminating homologous recombination. Data from the two present studies indicate that the TR2 region can oppose the activity of BRC, suggesting that BRCA2 contains regions that both favor and disrupt homologous recombination. These activities might operate at different stages of DNA repair.
Both reports also provide insight into how the opposing activities of BRCA2 can be regulated – a phosphorylation event at TR2 results in the loss of its interaction with RAD51, acting as a turn-off switch. These findings advance our knowledge of BRCA2’s role in genetic stability, and contribute to our understanding of why mutations in BRCA2 increase the likelihood of cancer.
Author contacts:
Stephen West (Cancer Research UK, London, UK) Author paper [16]
Tel: +44 1707 625 868; E-mail: stephen.west@cancer.org.uk

Luca Pellegrini (University of Cambridge, UK) Author paper [17]
Tel: +44 1223 333 662; E-mail: luca@cryst.bioc.cam.ac.uk


Deciphering the histone code
A method to identify all modifications on histones, the proteins around which DNA is packed, is presented online. This study should allow researchers a better understanding of how genes are regulated by alterations to these proteins.
DNA holds all the information for the building blocks of life, but how a cell reads this genetic information depends on histones, and in particular on modifications to these histones. For example, the attachment of methyl groups to histones usually signals that a gene is silent, whereas the attachment of acetyl groups corresponds to gene activation. Scientists have dubbed the combinatorial use of histone modifications the ‘histone code’, but the extent to which different modifications are combined in the histone code is still unknown.
To help crack the code, Neil Kelleher and colleagues devised a method to identify all the possible modifications that occur on histones in a cell. First they separated different histone variants, depending on their degree of acetylation and methylation, by hydrophilic interaction chromatography, then they applied high-resolution tandem mass spectroscopy to identify all modifications on each variant and the exact residues carrying them. By using a mass spectrometry technique known as ‘top down,’ in which intact proteins are fragmented inside the mass spectrometer, they observed better preservation of modifications than traditional mass spectrometry methods looking at pre-digested proteins. For one particular histone alone, they found over 150 different patterns of modification.
This method helps to decipher the elements that make up the histone code and will allow researchers to relate the pattern of these modifications to the regulation of gene activity.
Author contact:
Neil Kelleher (University of Illinois at Urbana-Champaign, IL, USA)
Tel: +1 217 333 5071; E-mail: kelleher@scs.uiuc.edu