Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA doublestrand break (DSB) repair, is often upregulated in cancer. POLQ is synthetic lethal with various DNA repair genes, including known cancer drivers such as BRCA1/2, making it essential in homologous recombination-deficient cancers. Thus, POLQ represents a promising target in cancer therapy and efforts for the development of POLQ inhibitors are actively underway with first clinical trials due to start in 2021. This review summarizes the journey of POLQ from a backup DNA repair enzyme to a promising therapeutic target for cancer treatment. POLQ: Exploiting a Cancer Vulnerability for TherapyTo increase efficiency and lower the burden of toxic side effects, a major goal of cancer therapy is to progress from a 'one-drug-fits-all' to an individualized treatment approach tailored to the tumor-specific molecular features. Two main targeted therapeutic strategies are currently utilized in cancer treatment, both exploiting cancer-specific vulnerabilities. In the first approach, therapeutic suppression of aberrantly upregulated oncogenes alleviates the growth advantage of cancer cells. The second approach is based on the phenomenon that genetic alterations acquired by tumor cells cause their dependency on other compensatory pathways, loss of which leads to synthetic lethality (see Glossary). Therefore, therapeutic inhibition of pathways that are synthetic lethal with a cancer-specific alteration evokes cellular death in tumor cells while leaving normal cells unharmed [1]. The recent advent of genome-wide genetic interaction studies has demonstrated the extensive number of synthetic lethal interactions in cancer, many of which can potentially be translated to targeted cancer therapies [2].Cancer cells frequently acquire mutations in DNA repair genes and respond by rewiring their DNA repair network to utilize compensatory pathways for survival. Dependency on compensatory DNA repair pathways opens room for the development of cancer-specific small molecule inhibitors. A group of successful drugs that use this mode of action are poly(ADP-ribose) polymerase (PARP) inhibitors, approved for the treatment of BRCA-deficient cancers. The essentiality of PARP for cancer cells with loss-of-function mutations in BRCA1/2 is remarkable as such cancer cells are up to 1000 times more sensitive to PARP inhibitors than healthy cells [3,4]. Although challenges such as the acquisition of drug resistance need to be faced, the clinical success of inhibitory drugs targeting DNA repair enzymes is highly encouraging. In this context, the DNArepair enzyme polymerase θ (POLQ) has received increasing attention. POLQ is upregulated in numerous cancers and its overexpression is associated with poor prognosis [5][6][7][8][9]. Moreover, synthetic lethal interactions between POLQ and multiple DNA repair genes, including factors involv...

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6 -knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11 + CTLA-4 + vesicles in DEF6 -mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.