A team led by Prof. ZHAO Guoping from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences has discovered for the first time that radiation induces the translocation of mitochondrial HIGD1A, an important mitochondrial protein, to the nucleus and promotes homologous recombination and radiation resistance, according to a study published in Oncogene.

It is of great significance to analyze the role of mitochondria in radiation sensitivity and to develop new radiosensitizers.  

Radiation-induced DNA damage response is the theoretical basis of radiotherapy. How to improve the sensitivity of tumor to radiation is the key factor of clinical radiotherapy. Mitochondria are one of the important organelles tightly bound together and show cellular responses to various stressors, including DNA damage.  

Recent studies have found that the mitochondrial factor HIGD1A translocates from the mitochondria to the nucleus under severe stress, suggesting that it may play critical extramitochondrial moonlighting roles in DNA damage repair pathway, but the specific mechanism remains clear.

In this study, using bioinformatics analysis, RNA sequencing, liquid chromatography-tandem mass spectrometry and other techniques, the researchers found that DNA damage-induced of mitochondrial factor HIGD1A translocates into the nucleus, modulates homologous recombination, and affects the sensitivity of multiple tumor cell lines to radiation therapy.  

This study demonstrates a novel regulatory role of HIGD1A in DNA damage repair by dynamically regulating the binding of replication protein A1 (RPA1) to SSDNA and timely removing RPA1 from the DNA double-strand break site. In addition, clinical inhibitors and in vivo studies have demonstrated the radiosensitization of HIGD1A.  

Taken together, these results provide compelling evidence that HIGD1A is a promising target for radiotherapy to sensitizing cancer.  

This work was supported by the National Natural Science Foundation of China, and the Director's Fund of HFIPS.

Schematic illustration of the mechanism of HIGD1A regulating homologous recombination. (Image by CHEN Bin)