Structural studies and biomedical applications of Three prime repair exonuclease 2(TREX2)

• Main Authors: Cheng, Hiu Lo, 鄭曉鷺
• Other Authors: Hsiao, Yu-Yuan
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/jhwr9t

碩士 === 國立交通大學 === 生物資訊及系統生物研究所 === 106 === Three prime repair exonuclease 2 (TREX2) and its homologous protein, TREX1, provide the major 3' to 5' exonuclease activity in mammalian cells. TREX2 belongs to DEDDh superfamily, and most members in this family are involved in various DNA/RNA metabolic pathways. Previous studies had shown that the natural substrate of TREX2 is probably double-stranded DNA and TREX2 is responsible for removing the 3' mismatched region of DNA duplex. The dsDNA processing ability of TREX2 may be related to chromosomal DNA repair and maintenance of genomic stability. Dysfunctional TREX2 will increase the chance of drug-induced or UV-induced skin cancer. However, the actual roles of TREX2 in maintaining genome integrity and the molecular mechanisms of TREX2 in binding and processing of dsDNA substrates are remain unclear. In this study, we used in vitro biochemical assays and TREX2-dsDNA complex structures to understand the catalytic properties of TREX2 on dsDNA substrates. Our structures indicate that TREX2 prefers to bind and process duplex DNA with longer double strand region. The structural observation is consistence with nuclease activity assays and previous in vivo studies. The structural features of TREX2-dsDNA complex can also be applied into classification of DEDDh exonucleases, which is useful for understand the cellular functions of other DEDDh exonucleases. On the other hand, overexpression of TREX2 is a hallmark of an immune‐mediated skin disease, psoriasis. In TREX2 knock-out mouse, the psoriatic symptom is dramatic decreased, which indicates the activity of TREX2 may shapes the psoriatic phenotype. Therefore, TREX2 is a potential drug targets for treating psoriasis. Recently, we had found some effective inhibitors of TREX2 by activity assays and determined one TREX2-inhibitor complex structure, which are pay the way for TREX2 related drug develop in psoriasis treatment.