Two related tumor suppressor genes, BRCA1 and BRCA2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review, we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanisms of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on the mechanisms of DNA damage repair where these proteins are involved, and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also discuss a hypothesis explaining why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss prospective novel therapeutic approaches for treating BRCAness cancers.

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

The persisting presence of opportunistic pathogens like Pseudomonas aeruginosa poses a significant threat to many immunocompromised cancer patients with pulmonary infections. This review highlights the complexity of interactions in the host’s defensive eicosanoid signaling network and its hijacking by pathogenic bacteria to their own advantage. Human lipoxygenases (ALOXs) and their mouse counterparts are integral elements of the innate immune system, mostly operating in the pro-inflammatory mode. Taking into account the indispensable role of inflammation in carcinogenesis, lipoxygenases have counteracting roles in this process. In addition to describing the structure-function of lipoxygenases in this review, we discuss their roles in such critical processes as cancer cell signaling, metastases, death of cancer and immune cells through ferroptosis, as well as the roles of ALOXs in carcinogenesis promoted by pathogenic infections. Finally, we discuss perspectives of novel oncotherapeutic approaches to harness lipoxygenase signaling in tumors.

ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that radically changed properties of the encoded BetaM proteins, which function as Na,K-ATPase subunits in lower vertebrates and birds. Eutherian BetaM has lost its ancestral function and became a muscle-specific resident of the inner nuclear membrane. Our earlier work implicated BetaM in regulation of gene expression through direct interaction with the transcriptional co-regulator SKIP. To gain insight into evolution of BetaM interactome we performed expanded screening of eutherian and avian cDNA libraries using yeast-two-hybrid and split-ubiquitin systems. The inventory of identified BetaM interactors includes lamina-associated protein LAP-1, myocyte nuclear envelope protein Syne1, BetaM itself, heme oxidases HMOX1 and HMOX2; transcription factor LZIP/CREB3, ERGIC3, PHF3, reticulocalbin-3 and β-sarcoglycan. No new interactions were found for chicken BetaM and human Na,K-ATPase β1, β2 and β3 isoforms, indicating the uniqueness of eutherian BetaM interactome. Analysis of truncated forms of BetaM indicates that residues 72-98 adjacent to the membrane in nucleoplasmic domain are important for the interaction with SKIP. These findings demonstrate that evolutionary alterations in structural and functional properties of eutherian BetaM proteins are associated with the increase in its interactome complexity.