Abstract
Simple SummaryHomologous recombination (HR) is a DNA repair pathway essential to genome stability and mutations in many HR genes are correlated with cancer predisposition. Transgenic mouse models are critical to establish HR factors as tumor suppressor genes. However, investigating the effects of suppressing HR genes in vivo is challenging because invalidation of most of them leads to embryonic lethality in mammals. To tackle this issue, elaborated alternative strategies have been developed. Here we review these alternative HR-defective mouse models and reveal the impact of HR defects on tumorigenesis. We highlight that the central HR factor, RAD51, has yet to be well characterized in vivo and, unlike most HR factors, its inactivation has not been associated with cancer predisposition, revealing what we call the “RAD51 paradox”. Finally, we discuss the use of mouse models to develop targeted cancer therapies as well as to understand the mechanisms of HR inactivation-driven tumorigenesis in vivo.Homologous recombination (HR) is a fundamental evolutionarily conserved process that plays prime role(s) in genome stability maintenance through DNA repair and through the protection and resumption of arrested replication forks. Many HR genes are deregulated in cancer cells. Notably, the breast cancer genes BRCA1 and BRCA2, two important HR players, are the most frequently mutated genes in familial breast and ovarian cancer. Transgenic mice constitute powerful tools to unravel the intricate mechanisms controlling tumorigenesis in vivo. However, the genes central to HR are essential in mammals, and their knockout leads to early embryonic lethality in mice. Elaborated strategies have been developed to overcome this difficulty, enabling one to analyze the consequences of HR disruption in vivo. In this review, we first briefly present the molecular mechanisms of HR in mammalian cells to introduce each factor in the HR process. Then, we present the different mouse models of HR invalidation and the consequences of HR inactivation on tumorigenesis. Finally, we discuss the use of mouse models for the development of targeted cancer therapies as well as perspectives on the future potential for understanding the mechanisms of HR inactivation-driven tumorigenesis in vivo.
Highlights
Homologous recombination (HR) is a molecular process highly conserved through evolution that plays prominent roles in genome plasticity
Inactivation of Xrcc2, Brca2 or the RAD51-loading function of BRCA1 leads to the formation of different types of tumors compared to Brca1 mouse models that, in addition, abrogate double-strand breaks (DSBs) resection, showing that different modes of tumorigenesis exist depending on how HR is invalidated
Transgenic mouse models have been key allies in the development and understanding of targeted therapy for HR-deficient tumors. They revealed that HR genes play essential roles in the suppression of tumorigenesis and showed that the modality of tumor predisposition depends on how HR is disrupted
Summary
Homologous recombination (HR) is a molecular process highly conserved through evolution that plays prominent roles in genome plasticity. Since replication stress is a prominent endogenous source of DNA damage and genome instability, these data indicate a causal role of DNA replication stress in the early steps of tumor initiation [18,19,20]. Because of its essential roles in genome stability maintenance, in response to replication stress, HR is generally considered a tumor suppressor mechanism. Investigations on the effects of HR suppression in vivo have been challenging due to the fact that most HR genes are essential in mammals, and as such, their knockout leads to embryonic lethality To tackle this issue, elaborated alternative strategies have been developed, and many mouse models have been designed to experimentally address the impact of HR defects on cancer development in vivo. We present mouse models of HR deficiency and discuss how they contribute to the understanding of HR-driven tumorigenesis and the development of targeted therapies for HR-inactivated tumors
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