Function of a DNA repair helicase in mitosis and its impact on rare genetic diseases – MitoRare

Protein science has moved from a focus on individual molecules with monofunctional specialties to an integrated perspective in which they emerge as dynamic actors with multiple functions. Among the multifunctional proteins is XPD, a DNA helicase involved in gene expression, maintenance of genome integrity but also during cell division. Indeed, XPD can be found in a large complex called TFIIH in which it participates both in the transcription of genes encoding proteins and in the repair of bulky DNA lesions. At the same time, recent observations, particularly in Drosophila, revealed that XPD could also be found in other complexes independent of TFIIH, which would lead it to participate in cell division and more particularly in mitosis. However, to date, the mode of action as well as the mitotic function of XPD remain largely misunderstood, particularly in humans.
A better understanding of the functions of XPD is of great importance because mutations within XPD are at the origin of several autosomal recessive diseases in humans, pathologies with multiple phenotypes and of still largely unexplained origins. Thus, and taking into account the various functions performed by XPD, it is possible that these patients suffer from certain symptoms originating from a disturbance during cell division.
The objective of this project is therefore to better understand the role of XPD during mitosis and will rely on the strong skills of the teams with both this protein and cell division. We will base our project on preliminary results which have already shown that XPD interacts with a motor protein required for the establishment of the mitotic spindle. We have further found that human cells carrying an XPD mutation exhibit a large number of mitotic defects which are restored upon expression of a normal form of XPD. The involvement of XPD in cell division will also have important implications for understanding this essential cellular process in normal cells.