Translational research in radiation-induced DNA damage signaling and repair

Abstract

Radiotherapy is an effective tool in the fight against cancer. It is non-invasive and painless, and with advanced tumor imaging and beam control systems, radiation can be delivered to patients safely, generally with minor or no adverse side effects, accounting for its increasing use against a broad range of tumors. Tumors and normal cells respond to radiation-induced DNA damage by activating a complex network of DNA damage signaling and repair pathways that determine cell fate including survival, death, and genome stability. DNA damage response (DDR) proteins represent excellent targets to augment radiotherapy, and many agents that inhibit key response proteins are being combined with radiation and genotoxic chemotherapy in clinical trials. This review focuses on how insights into molecular mechanisms of DDR pathways are translated to small animal preclinical studies, to clinical studies of naturally occurring tumors in companion animals, and finally to human clinical trials. Companion animal studies, under the umbrella of comparative oncology, have played key roles in the development of clinical radiotherapy throughout its >100-year history. There is growing appreciation that rapid translation of basic knowledge of DNA damage and repair systems to improved radiotherapy practice requires a comprehensive approach that embraces the full spectrum of cancer research, with companion animal clinical trials representing a critical bridge between small animal preclinical studies, and human clinical trials.

Feline XLF accumulates at DNA damage sites in a Ku‐dependent manner

“…Unfortunately, about 6 million dogs and a similar number of cats are diagnosed with cancer in the USA each year [1]. Nickoloff et al [2] described that companion animal studies, under the umbrella of comparative oncology, have played key roles in the development of clinical radiotherapy throughout its more than 100-year history. They also mentioned that canine cancer models present many translational research opportunities to exploit fundamental knowledge about DNA repair to improve radiotherapy [2].…”

Molecular Signaling in Response to Charged Particle Exposures and its Importance in Particle Therapy

“…That damage is difficult to repair and affects rejoining faithfulness [13][14][15]. DNA repair systems have an intrinsic weakness in processing complex damages [16]. Molecular signaling in response to charged-particle exposure is predominantly a DNA damage response (DDR), turning the switch toward cellular survival or death ( Figure 2).Ionizing radiation activates phosphatidylinositol-3-kinase-related enzymes, including ataxia telangiectasia mutant (ATM), ataxia telangiectasia, Rad3-related protein (ATR), and DNA-dependent protein kinase (DNA-PK) [21].…”

“…Molecular signaling in response to charged-particle exposure is predominantly a DNA damage response (DDR), turning the switch toward cellular survival or death ( Figure 2).Ionizing radiation activates phosphatidylinositol-3-kinase-related enzymes, including ataxia telangiectasia mutant (ATM), ataxia telangiectasia, Rad3-related protein (ATR), and DNA-dependent protein kinase (DNA-PK) [21]. The ATM and ATR are recruited to complex double-strand breaks (DSBs) (Figure 3) [22].Mutations in ATM cause radiation hypersensitivity in patients with the autosomal recessive disorder ataxia-telangiectasia [16]. Mice with ATM haploinsufficiency develop cataracts earlier compared with wild-type animals, and the enhanced sensitivity was greater for high-LET heavy ions compared with low-LET x-rays [23].There are 4 autophosphorylation sites in ATM: Ser-367, Ser-1893, Ser-1981, and Ser-2996.…”

“…That damage is difficult to repair and affects rejoining faithfulness [13][14][15]. DNA repair systems have an intrinsic weakness in processing complex damages [16]. Molecular signaling in response to charged-particle exposure is predominantly a DNA damage response (DDR), turning the switch toward cellular survival or death ( Figure 2).…”

“…Mutations in ATM cause radiation hypersensitivity in patients with the autosomal recessive disorder ataxia-telangiectasia [16]. Mice with ATM haploinsufficiency develop cataracts earlier compared with wild-type animals, and the enhanced sensitivity was greater for high-LET heavy ions compared with low-LET x-rays [23].…”