1980年代に行われた研究によって、XR-1と呼ばれるCHO細胞変異株は、細胞周期のG1期でのγ線照射に対する感受性が極めて高い一方、S期終盤でのγ線損傷に対する耐性はほぼ正常であることが示された[33]。そして、XR-1の細胞周期感受性は、電離放射線照射や制限酵素によって形成されたDNA二本鎖切断の修復の欠陥と関係していることが示された[33][34][35]。XR-1細胞とヒト線維芽細胞との体細胞ハイブリッドを用いた研究ではXR-1変異は劣性変異であることが示され[35]、その後の染色体解析ではヒトの相補性遺伝子は5番染色体にマッピングされた[36]。このヒト遺伝子はXRCC4(X-ray-complementing Chinese hamster gene 4)との仮称がつけられ、このXRCC4遺伝子はγ線照射やブレオマイシンに対する耐性を生化学的に正常レベルにまで回復すること、そしてDNA二本鎖切断修復能力を回復することが明らかにされた[36]。こうした知見に基づき、XRCC4はXR-1表現型の原因となる単一の遺伝子であることが提唱された[36]。
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