The Team of Sci Adv Zhou Pingkun found a new mechanism for TIP60 SUMO modification to regulate the selection of DNA double-stranded fracture repair pathways and tumor radiation chemotherapy sensitivity.

In the treatment of cancer, radiotherapy and some chemotherapeutic drugs such as PARP inhibitors can cause DNA damage, especially double strand breaks.by targeting the DNA repair function of tumor cells and its cell cycle dependent mechanism, DNA damage of cancer cells can not be completely repaired after radiotherapy and chemotherapy, thus inducing tumor cell death, which is one of the biological technology ways to improve the clinical effect of tumor treatment.therefore, it is of great significance to conduct in-depth research on the mechanism of DNA damage repair for guiding the clinical practice of precise individual treatment of tumor.cell genomic DNA is always suffering from the external environment and various factors within the cell, resulting in various types of damage.among them, double strand break (DSB) damage is one of the most serious damage types, and a single DSB can lead to cell death.DSB is mainly repaired by two repair pathways: non homologous end joining (NHEJ) and homologous recombination (HR).NHEJ repair is a relatively rapid process, which directly connects two broken DSB ends through DNA ligase, which can be performed in all cell cycles except mitosis.compared with NHEJ repair, HR repair is a multi-step and complex process, and requires the existence of homologous DNA molecular template. More and more evidence shows that HR repair mainly occurs in S-phase cells and G2 phase cells, which is a faithful error free modification.how to choose the appropriate repair pathway to repair DSBs in different cell cycles is still unclear.recently, the team of Zhou pingkun, a researcher from the Institute of radiation medicine, Academy of Military Sciences, published a report entitled "Tip60 K430 sumoylation attenuations its interaction with DNA PKCs in S phase cells: facilitating homologous recombination and emerging target for cancer" in science advances Dr. Takayama is the first author of this paper.this study found that the level of SUMO2 modification at K430 site of Tip60 changed in a cell cycle dependent manner, and was in a highly sumo state in S phase cells.in S phase cells, this SUMO modification inhibits the interaction between Tip60 and DNA PKCs, which is the key repair protein of NHEJ pathway, and then weakens the activity of DNA PKCs kinase and NHEJ function, and promotes the homologous recombination repair pathway selected by S-phase cells.this study revealed for the first time the role and mechanism of Tip60 in the selection of DNA double strand break repair pathway, and developed new therapeutic targets for tumor radiotherapy and DNA damage chemotherapy drugs such as parpi. Animal experiments have proved that the targeted therapy strategy is effective.in this study, we found that the interaction between Tip60 and DNA PKCs, an important protein kinase in NHEJ repair pathway damaged by DSBs, was significantly weakened in S phase.in order to study its specific mechanism, we identified the respective domains of Tip60 binding with DNA PKCs. It was found that K430 site in the binding region of Tip60 and DNA-PKcs was highly conserved in evolution, and could be modified by SUMO2, and was cell cycle dependent: Tip60 was highly sumoyed in S phase cells.this study identified that Tip60 SUMO2 modified E3 and de sumo enzymes were pias4 and senp3, respectively. Sumo and de sumo experiments in vitro showed that the SUMO2 modification of Tip60 K430 site could directly block the binding site of Tip60 and DNA PKCs, thus inhibiting the binding of Tip60 and DNA PKCs.this study also confirmed that the phosphorylation level of DNA PKCs kinase s2056 in S phase cells of Tip60 k430r mutation was abnormally increased, the activity of HR repair pathway was inhibited, and the sensitivity of cancer cells and tumor tissues to radiation and DNA damage chemotherapy drugs such as PARP inhibitors was significantly increased.this study has important guiding significance for reducing tumor resistance to drugs and radiotherapy, as well as precise anti-cancer therapy in the future.the research team recently published another research paper on the selection mechanism of DNA double strand break repair in G1 phase, entitled "rbx1 prompt degradation of Exo1 to limit the homologous recombination pathway of DNA double strand break repair in G1 phase", It was revealed that DNA PKCs restricted the function of exonuclease Exo1 by activating the ubiquitin ligase mechanism of rbx1-scf E3 in G1 phase cells, thus avoiding G1 cells from starting HR repair pathway. Because G1 cells lack homologous DNA templates, HR repair of DNA double strand breaks can not be carried out.original link: