Key Regulating Protain Found in Homologous Recombination and Cell Survival

Feb 25, 2022 | By CHEN Bin, ZHAO Weiwei

According to a research published in Oncogene recently, a team led by Prof. Zhao Guoping from Hefei Institutes of Physical Science (HFIPS), Chinese Academy of Sciences (CAS) found, for the first time, that Radiation induced the translocation of mitochondrial HIGD1A, an important mitochondrial protein, to the nucleus, and promoted Homologous Recombination and radio-resistance.  

This is of great significance for analyzing the role of mitochondrial in radiation sensitivity, and the development of new radiosensitizers.

Radiation-induced DNA damage response is the theoretical basis of radiotherapy, and how to improve the sensitivity of tumors to radiation is the key factor in clinical radiotherapy. Mitochondria are among the vital cell organelles that are tightly integrated 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 the DNA damage repair pathway, but the specific mechanism is not clear.

In this study, by using bioinformatics analysis, RNA Sequencing, Liquid Chromatography with Tandem Mass Spectrometry and other techniques, researchers found that DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and affects sensitivity to radiation therapeutics in multiple tumor cell lines. This study demonstrated a novel regulatory role of HIGD1A in DNA damage repair through dynamically regulating Replication Protein A1 (RPA1)-ssDNA binding and timely removing RPA1 from DNA Double Strand Breaks sites. In addition, clinical inhibitor, and in vivo studies confirmed the radio-sensitizing effect of HIGD1A.

Collectively, these results provide convincing evidence that HIGD1A serves as a promising target to sensitize cancer to radio-therapy.

This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the HFIPS Director’s Fund. The NMR work was performed on the NMR spectrometer system of the Steady State High Magnetic Field Experiment Facility (SHMFF).

Schematic illustration of the mechanism of HIGD1A regulating HR (Image by CHEN Bin)

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