The cellular machinery coordinating responses to DNA damage is critically important to ensure that cells with potentially deleterious defects do not progress through the cell cycle and promote malignant transformation. To this end, the ATR-activated CHK1 kinase has key functions in the nucleus upon recognition of replication stress at stalled DNA replication forks by triggering a signaling cascade that halts the cell cycle. However, the roles for this kinase pair outside the nucleus are less well understood, and a non-canonical function specific to the immune response has not been explored previously. Using cutting-edge biochemistry, super-resolution imaging, and cellular and in vivo immunology approaches, two specific aims will be pursued.
Aim 1) To define the molecular connections between CHK1 and T cell receptor (TCR) signaling molecules and their roles in T cell activation in vivo.
Aim 2) To evaluate analogous signaling roles for CHK1 in related receptors of the immune in order to pinpoint its mechanism of action. These studies are expected to yield fundamental insights into roles for CHK1, heretofore presumed to function primarily in the nucleus, in cytoplasmic immunoreceptor signaling events and define the impact of these roles on immunity. The broader implications of these studies include novel insights into potential effects of ATR and CHK1 inhibitors, currently under evaluation in cancer clinical trials, on the immune system. These insights may be beneficial in mitigating unexpected effects of these drugs and maximizing the potential to target ATR/CHK1 or novel downstream mediators therapeutically in diseases of the immune system. !
The experiments proposed here focus on novel and non-canonical roles for the DNA damage response kinase CHK1 in activation of immune responses. Perturbation of cellular responses to DNA damage can affect risk of cancer development through genomic derangements, and understanding the fundamental pathways for immune activation has important implications for protection from infection, cancer, and autoimmune disorders. These studies will have broad public health relevance by building our knowledge of how the DNA damage response proteins and immune signaling proteins functionally interrelate. !
