On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations

Abstract Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER), which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH) and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs). The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer. The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools.

Size matters: saccades during scene perception

We investigated the effect of image size on saccade amplitudes. First, in a meta-analysis, relevant results from previous scene perception studies are summarised, suggesting the possibility of a linear relationship between mean saccade amplitude and image size. Forty-eight observers viewed 96 colour scene images scaled to four different sizes, while their eye movements were recorded. Mean and median saccade amplitudes were found to be directly proportional to image size, while the mode of the distribution lay in the range of very short saccades. However, saccade amplitudes expressed as percentages of image size were not constant over the different image sizes; on smaller stimulus images, the relative saccades were found to be larger, and vice versa. In sum, and as far as mean and median saccade amplitudes are concerned, the size of stimulus images is the dominant factor. Other factors, such as image properties, viewing task, or measurement equipment, are only of subordinate importance. Thus, the role of stimulus size has to be reconsidered, in theoretical as well as methodological terms.