Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution.

DNA replication stress promotes genome instability in cancer. However, the contribution of the replication stress response to the development of malignancies remains unresolved. The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1. Notably, a quarter of the Smarcal1-deficient mice did not develop tumors. Moreover, hematopoietic stem/progenitor cells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage and apoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymus after IR. Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respond to other replication stress stimuli. Thus, our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.

Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells.

DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si)RNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.

Integrin function and signaling as pharmacological targets in cardiovascular diseases and in cancer.

The microenvironment is now considered as an important source of potential therapeutic targets in diverse pathologies. In cardiovascular diseases and in cancer, common processes involving stromal remodeling, cell invasion, and angiogenesis can promote progression of the pathology. At each step of the pathogenesis, cell adhesion needs to be modulated to allow adaptation of cell survival/motility/proliferation functions to the microenvironment. Among adhesion receptors, integrins, responsible for cell/matrix or cell/cell interactions, play a key role in the cellular responses. Moreover, their engagement conditions the sensitivity to apoptosis induced by therapeutic drugs. Targeting of the extracellular side of integrins in order to modulate their adhesive functions is under development and has reached clinical indications. However, improvement of oral availability and of cell signaling control is required in the future. Targeting of the extracellular or the intracellular key proteins involved in integrin-dependent signaling pathway seems promising. Yet, although some common key enzyme inhibitors are under development, a better knowledge of the specificity of integrin activation and interaction with partners upon pathogenesis is of major importance in envisaging the antagonism of integrin-linked signals as a therapeutic tool alone or in association with other therapies.