Structural insights into the duplex DNA processing of TREX2

Hiu Lo Cheng, Chun Ting Lin, Kuan Wei Huang, Shu-Ying Wang, Yeh Tung Lin, Shu Ing Toh, Yu Yuan Hsiao

Research output: Contribution to journalArticle

Abstract

The three prime repair exonuclease 2 (TREX2) is an essential 3-to-5 exonuclease that functions in cell proliferation, genome integrity and skin homeostasis maintenance. The abnormal expression level of TREX2 can result in broken chromosome, increased susceptibility to skin carcinogenesis and Psoriasis. However, the molecular mechanisms of how TREX2 binds and processes its natural substrates, dsDNA or chromosomal DNA, to maintain genome stability remain unclear. In this study, we present four new crystal structures: apo-TREX2, TREX2 in complex with two different dsDNA substrates, and TREX2 in complex with a processed dsDNA product. Analysis of the structures reveals that TREX2 stacks with the 5-terminal of dsDNA by a Leu20-Pro21-Asn22 cluster for precisely trimming the 3-overhang. In addition, TREX2 specifically interacts with the non-scissile strand of dsDNA by an -helix-loop region. The unique interaction patterns of the TREX2–dsDNA complex highlight the requirement of long double-stranded region for TREX2 binding and provide evidence of the functional role of TREX2 in processing chromosomal DNA. Moreover, the non-processive property of TREX2 is elucidated by the structure of TREX2–product complex. Our work discloses the first structural basis of the molecular interactions between TREX2 and its substrates and unravels the mechanistic actions of TREX2.

Original languageEnglish
Pages (from-to)12166-12176
Number of pages11
JournalNucleic acids research
Volume46
Issue number22
DOIs
Publication statusPublished - 2018 Jan 1

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Exonucleases
DNA
Skin
Genomic Instability
Psoriasis

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Cheng, H. L., Lin, C. T., Huang, K. W., Wang, S-Y., Lin, Y. T., Toh, S. I., & Hsiao, Y. Y. (2018). Structural insights into the duplex DNA processing of TREX2. Nucleic acids research, 46(22), 12166-12176. https://doi.org/10.1093/nar/gky970
Cheng, Hiu Lo ; Lin, Chun Ting ; Huang, Kuan Wei ; Wang, Shu-Ying ; Lin, Yeh Tung ; Toh, Shu Ing ; Hsiao, Yu Yuan. / Structural insights into the duplex DNA processing of TREX2. In: Nucleic acids research. 2018 ; Vol. 46, No. 22. pp. 12166-12176.
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Cheng, HL, Lin, CT, Huang, KW, Wang, S-Y, Lin, YT, Toh, SI & Hsiao, YY 2018, 'Structural insights into the duplex DNA processing of TREX2', Nucleic acids research, vol. 46, no. 22, pp. 12166-12176. https://doi.org/10.1093/nar/gky970

Structural insights into the duplex DNA processing of TREX2. / Cheng, Hiu Lo; Lin, Chun Ting; Huang, Kuan Wei; Wang, Shu-Ying; Lin, Yeh Tung; Toh, Shu Ing; Hsiao, Yu Yuan.

In: Nucleic acids research, Vol. 46, No. 22, 01.01.2018, p. 12166-12176.

Research output: Contribution to journalArticle

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Cheng HL, Lin CT, Huang KW, Wang S-Y, Lin YT, Toh SI et al. Structural insights into the duplex DNA processing of TREX2. Nucleic acids research. 2018 Jan 1;46(22):12166-12176. https://doi.org/10.1093/nar/gky970