Molecular genetics

We have shown that ASCIZ and DYNLL1 are required for normal B cell development in mice, and also for the optimisation of antibody genes during the immune response of mature B cells. A main target of the ASCIZ-DYNLL1 axis during development is the cell death protein BIM whose activity is dampened directly by DYNLL1 binding. In mature B cells, and to some extent also in developing B cells, DYNLL1 promotes the oligomerisation of the key DNA repair protein 53BP1 which regulates the efficiency of antibody gene diversification by the non-homologous end-joining pathway. We recently found that the ASCIZ-DYNLL1 axis also plays a key role in regulating the activation of mature B cells in a highly signal-specific manner, and we are currently determining the underlying cellular mechanisms and their impact on antibody-mediated immune responses in mice.

In line with its original identification as a light chain of various Dynein complexes, we found that loss of DYNLL1 destabilizes the Dynein-2 complex that is specifically involved in the retrograde transport of signaling components from a small antenna-like structure, the primary cilium, present on most non-haematopoietic cells. Consequently, targeted removal of the Dynll1 gene in the limbs of developing mice mimics the severe bone shortening characteristic of a life-threatening human disorder with inherited Dynein-2 subunit mutations, Short-rib thoracic dystrophy/Jeune syndrome. In contrast to mice that completely lack DYNLL1, ASCIZ-deleted mice – which still contain about 10% of normal DYNLL1 protein levels – have almost normal bones, indicating that even very low residual DYNLL1 levels are sufficient for largely normal Dynein-2 complex activity. Our bone-specific DYNLL1-deleted mice currently represent the only viable animal model for Jeune syndrome, and provide a valuable tool for the exploration of potential therapeutic approaches.

One of the best-known targets of DYNLL1 is 53BP1, which plays a key role in directing the repair of DNA double-strand breaks towards the mutagenic non-homologous end-joining pathway and in this way promotes the therapeutic response of BRCA1-mutated breast and ovarian cancers to PARP inhibitors. Consequently, ASCIZ and DYNLL1 have recently also been identified as mediators of PARP inhibitor sensitivity in several functional genetic screens, consistent with their supportive role in 53BP1-mediated antibody gene rearrangements in B cells (see our other Research Theme). We have previously shown that ASCIZ also has a separate role as a DNA damage response factor that depends on DYNLL1 but is independent of its function as a transcription factor. Ongoing work in the laboratory investigates how these two roles of ASCIZ cooperate in the onset of cancer development in mice, and in the response of established cancer cells to chemotherapeutics.