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The Korean Society for Biotechnology and Bioengineering (한국생물공학회)
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Trends in Protein Engineering for Gene Targeting: Homing Endonucleases and Zinc Finger Nucleases

유전자 표적화를 위한 단백질공학 연구동향: Homing Endonucleases and Zinc Finger Nucleases

  • Cheong, Dea-Eun (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Kim, Geun-Joong (Department of Biological Sciences, College of Natural Sciences, Chonnam National University)
  • Received : 2010.04.21
  • Accepted : 2010.06.19
  • Published : 2010.06.30
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Abstract

Monogenic diseases are resulted from modifications in a single gene of human cells. Because their treatment with pharmacological medicine have a temporary effect, continuous nursing care and retreatment are required. Gene therapy, gene targeting and induced pluripotent stem cell (iPSC) are considered permanent treatment methods of them. In gene therapy, however, retroviral vectors that have potential toxicity caused by random insertion of harmful virus are used as vehicles for transferring genetic materials. On the other hand, gene targeting could replace and remove the modified gene though homologous recombination (HR) induced by site-specific endonucleases. This short review provides a brief overview on the recently tailored endonucleses with high selectivity for HR.

Monogenic disease의 치료를 위한 하나의 전략으로 viral vector를 이용한 gene therapy에 비해 독성이 적은 gene targeting 기술을 이용하기 위한 연구가 진행되고 있다. 이러한 연구의 주된 관점은 자연적인 HR의 낮은 효율을 개선하기 위한 DSB 유도 방법으로, 선택성을 높일 수 있는 긴 염기서열의 인식이 가능한 artificial endonuclease의 개발이다. 본 글에서는 이러한 artificial endonuclease 중, 가장 많이 연구 되고 있는 homing endonuclease와 zinc finger nuclease를 간략히 소개하였다. 전자와 후자 모두, 인식 서열에 대한 일정 수준의 tolerance (인식 서열 일부가 특이적이지 않아 다른 염기로 구성된 경우)가 존재하여, 일정한 비율로 다른 target을 절단할 수 있는 가능성이 존재한다. 이러한 점은, meganucleases를 치료 목적으로 이용할 때 세포 독성을 나타내는 근본원인 중 하나이다. 두 종 모두 이러한 특성을 가짐에도 불구하고, 완전한 비자연적인 후자보다는 전자의 경우가 보다 효과적이며 낮은 세포독성을 보이는 것으로 보고되고 있다. 물론 실험 조건이나 적용되는 세포 종류, 인위적인 단백질의 발현 정도에 따라 세포 독성유무 또는 정도에 차이가 나타남이 확인되고 있다. 이러한 사실들에 근거할 때, gene targeting을 유도하기 위한 artificial endonuclease의 서열 특이성을 증대시키는 것이 가장 중요하나, 그 외 여러 인자들에 대한 복합적인 연구 역시 필요함을 보여준다. 현재까지 실제 치료제로 쓰인 예는 없지만, 시험관내에서 보이는 결과와 모델 개체에서 이루어진 표적화정도, 관련된 단백질 치료제들이 지닌 잠재성을 비교할 때 매우 큰 가능성을 지니고 있음은 충분히 확인할 수 있다.

Keywords

References

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