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The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable

Stephanie S Tseng-Rogenski1, Koji Munakata1, Daniel Y Choi1

  • 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Molecular and Cellular Biology
|April 15, 2020
PubMed

Insights

Mutations in MutS homolog 3 (MSH3) affect colorectal cancer (CRC) progression. Inflammation causes MSH3 to move out of the nucleus, increasing DNA damage and promoting cancer growth, especially in EMAST-positive CRCs.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • DNA mismatch repair (MMR) inactivation drives colorectal cancer (CRC) tumorigenesis.
  • Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in CRCs correlate with reduced nuclear MutS homolog 3 (MSH3) and poor prognosis.
  • Interleukin-6 (IL-6) induces reversible MSH3 nuclear export, suggesting MSH3 is a shuttling protein.

Purpose of the Study:

  • To investigate the functional roles of MSH3 nuclear localization signals (NLS1-3) and nuclear export signals (NES1-2).
  • To determine the impact of a common 27-bp deletion (Δ27bp) near NLS1 on MSH3 localization and function.
  • To elucidate the mechanism by which MSH3 shuttling influences EMAST and DNA damage in CRC.

Main Methods:

  • Site-directed mutagenesis of MSH3 putative NLS and NES.
  • Assessment of MSH3 nuclear import and export functions in response to IL-6.
  • Analysis of MSH3 localization in CRC cells with and without the Δ27bp deletion under oxidative stress.

Main Results:

  • NLS1 and NLS2 mediate nuclear import, with NLS1 being critical for full-length MSH3 nuclear localization.
  • NES1 and NES2 function synergistically for nuclear export, both required for IL-6-induced MSH3 export.
  • The Δ27bp deletion in MSH3 compromises NLS1 function, leading to cytoplasmic localization under oxidative stress.

Conclusions:

  • MSH3 shuttling between the nucleus and cytoplasm is regulated by specific NLS and NES motifs.
  • Inflammation-induced MSH3 cytoplasmic accumulation reduces nuclear MSH3, promoting EMAST and DNA damage in CRC.
  • Polymorphisms near MSH3's NLS1 may enhance cytosolic retention, impacting inflammation-associated neoplastic processes.
Keywords:
EMASTIL-6MSH3colorectal cancerinflammationmismatch repairnuclear import/exportsubcellular localization

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