Modeling the Study of DNA Damage Responses in Mice

Abstract

SummaryDamaged DNA has a profound impact on mammalian health and overall survival. In addition to being the source of mutations that initiate cancer, the accumulation of toxic amounts of DNA damage can cause severe developmental diseases and accelerate ageing. Therefore, understanding how cells respond to DNA damage has become one of the most intense areas of biomedical research in the recent years. However, whereas most mechanistic studies derive from in vitro or in cellulo work, the impact of a given mutation on a living organism is largely unpredictable. For instance, why BRCA1 mutations preferentially lead to breast cancer whereas mutations compromising mismatch repair drive colon cancer is still not understood. In this context, evaluating the specific physiological impact of mutations that compromise genome integrity has become crucial for a better dimensioning of our knowledge. We here describe the various technologies that can be used for modeling mutations in mice, and provide a review of the genes and pathways that have been modeled so far in the context of DNA damage responses.

DNA mismatch repair and the DNA damage response

“…Although much has been deduced from the use of established tumor cell lines deficient for MMR, tunable promoters and gene targeting approaches such as the CRISPR/Cas9 system are gaining wide use as are rapidly advancing imaging techniques [158,159]. Finally, in vivo studies provide a critical testing ground [160,161]. Collectively, these approaches are poised to reveal novel insights into the functions of the MMR system in the DNA damage response.…”

Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma

“…Mouse models have allowed groups to study the physiological functions of DSB repair proteins and to characterize their roles in protecting against cancer ( 44 ). Studies using mouse models examining the role of the DDR machinery in modulating liver carcinogenesis are limited, but previous reports have implicated the Ku heterodimer in protecting against liver tumorigenesis.…”

Ablating Ku70 phosphorylation results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma

“…Mouse models have allowed groups to study the physiological functions of DSB repair proteins and to characterize their roles in protecting against cancer (Specks et al, 2015). The majority of these studies have utilized knockout of the perspective gene, with limited studies using mouse models with point mutations in DSB repair proteins.…”