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A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway

Hao-Ming Chang1, Robinson Triboulet, James E Thornton

  • 1Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA.

Nature
|April 19, 2013
PubMed

Insights

The pluripotency factor Lin28 inhibits let-7 microRNA production. Researchers identified Dis3l2 as the enzyme degrading uridylated pre-let-7, uncovering a new RNA decay pathway crucial for development and cancer.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Biology

Background:

  • Lin28 is a pluripotency factor inhibiting let-7 microRNA (miRNA) expression in undifferentiated cells.
  • Lin28 acts as an oncogene in certain cancers by blocking let-7 miRNA biogenesis.
  • Lin28 recruits uridylyl transferases to pre-let-7 RNAs, leading to their degradation by an unknown RNase.

Purpose of the Study:

  • To identify the specific RNase responsible for the degradation of uridylated pre-let-7.
  • To elucidate the role of 3' oligouridylation as an RNA decay signal.
  • To investigate the physiological relevance of this pathway in development and disease.

Main Methods:

  • Biochemical reconstitution assays using purified proteins and RNA.
  • Knockdown of candidate RNases in mouse embryonic stem cells.
  • Analysis of pre-let-7 RNA stability and processing.

Main Results:

  • Dis3l2, a 3'-5' exonuclease, was identified as the enzyme degrading uridylated pre-let-7.
  • 3' oligouridylation was shown to stimulate Dis3l2 activity in vitro.
  • Knockdown of Dis3l2 in mouse embryonic stem cells resulted in pre-let-7 stabilization.

Conclusions:

  • Dis3l2 is the primary nuclease responsible for the decay of uridylated pre-let-7.
  • 3' oligouridylation serves as a specific decay signal for Dis3l2.
  • This pathway is critical for regulating let-7 miRNA levels and has implications for Perlman syndrome and Wilms' tumor.

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