Induction of \u3cem\u3eIL19\u3c/em\u3e Expression through JNK and cGAS-STING Modulates DNA Damage–Induced Cytokine Production

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage–induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING–dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage

A dp53-Dependent Mechanism Involved in Coordinating Tissue Growth in Drosophila

A study in the Drosophila wing suggests a crucial role of p53 in the coordination of growth between adjacent cell populations to maintain organ proportions and shape

DNA repair, genome stability and cancer: a historical perspective

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies

Characterization and use of the interaction between ATR suppression and p53 deficiency

p53 influences a staggering array of cellular processes that ultimately impact diverse aspects of normal physiology. Importantly, the majority of human cancers are functionally deficient in p53, and loss of this critical tumor suppressor is often associated with resistance to conventional chemotherapy. Efforts to identify novel therapeutic approaches to p53-deficienct malignancies have suggested that the ATR-CHK1 pathway may be a useful target, as suppression of ATR or CHK1 is especially toxic to model organisms lacking p53. Unfortunately, the precise nature of this interaction has remained poorly understood and its potential for use in a therapeutic setting is currently unclear. This thesis presents a detailed characterization of a synthetic lethal interaction between complete ATR loss and p53 deficiency in non-malignant tissues and provides evidence that this deleterious outcome is partly the product of a non-cell autonomous interaction. These findings are then applied to the clinically relevant problem of p53-deficient malignancies in the development and use of a novel genetic system to conditionally suppress, rather than eliminate, ATR in adult tissues and model p53-deficient cancers

Characterization and use of the interaction between ATR suppression and p53 deficiency

p53 influences a staggering array of cellular processes that ultimately impact diverse aspects of normal physiology. Importantly, the majority of human cancers are functionally deficient in p53, and loss of this critical tumor suppressor is often associated with resistance to conventional chemotherapy. Efforts to identify novel therapeutic approaches to p53-deficienct malignancies have suggested that the ATR-CHK1 pathway may be a useful target, as suppression of ATR or CHK1 is especially toxic to model organisms lacking p53. Unfortunately, the precise nature of this interaction has remained poorly understood and its potential for use in a therapeutic setting is currently unclear. This thesis presents a detailed characterization of a synthetic lethal interaction between complete ATR loss and p53 deficiency in non-malignant tissues and provides evidence that this deleterious outcome is partly the product of a non-cell autonomous interaction. These findings are then applied to the clinically relevant problem of p53-deficient malignancies in the development and use of a novel genetic system to conditionally suppress, rather than eliminate, ATR in adult tissues and model p53-deficient cancers