Genomic DNA always comes under various sources of DNA damageattacks, such as UV in the natural environment, ROS under normal metabolism andso on. In order to maintain genomic stability, eukaryotes have evolved aprotection mechanism which is called DNA damage response. The DNA damage response is a kind of complicated signal transduction network system. It cansense the DNA damage, transfer signals and result in a series of responses which include cell cycle checkpoint, DNA repair, transcription change and even cell death.

Chk1 is the key kinases in genome stability supervision system. And it plays an important role in cell cycle checkpoint, DNA repair and cell survival process. The research group led by TANG Tieshan from Institute of Zoology of Chinese Academy of Sciences found that the disease-related proteins ATX3 in SCA3/MJDI are the important controller of Chk1 kinases stability. The deficiency of ATX3 would lead to the decline of Chk1 proteins, the G2/Mcheckpoint defect mediated by ATX3 and the increase of DNA damage sensibility. Further study found that, as the deubiquitin enzyme, ATX3 can antagonist the polyubiquitin and degradation of E3 ligase compounds DDB1/CUL4A and Chk1 mediated by FBXO6. The regulation of ATX3 tothe Chk1 stability is dynamic. In quiescent condition and early stage ofreplication stress, ATX3 combine with Chk1 and promote its stability. When under replication stress for a long time, ATX3 dissociate from Chk1 accompaniedby the increase of the combination of Chk1 and E3 ligase compounds. Then, E3ligases mediate Chk1 deubiquitin and degradation which would promote thetermination of checkpoint, the recovery of cell cycle and the survival of cells.

This research has not only found the important role of ATX3 in genomic stability maintenance through regulating Chk1, but also has contributed to clarify the molecular pathogenesis of SCA3/MJD1. Similar to Parkinson’s disease, the main pathological features of SCA3/MJD1 is the loss of dopaminergic neuron. The pathological mechanism of it is still unknown. The research result has an important significance to explore the DNA damage response in the role of dopaminergic neuron regression.

The research result has been published on NucleicAcid Research on Feb 9^th, 2017, titled as “ATX3 Promotes GenomeIntegrity by Stabilizing Chk1”.

Time: 2017-02-16

Source: Institute of Zoology