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siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells
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siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells

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RNAi-based screening identifies the Mms22L-Nfkbil2 complex as a novel regulator of DNA replication in human cells

Wojciech Piwko1, Michael H Olma, Michael Held

  • 1Institute of Biochemistry, Department of Biology, ETH Zurich, Zurich, Switzerland. wojciech.piwko@bc.biol.ethz.ch

The EMBO Journal
|November 30, 2010
PubMed

Insights

The Mms22L-Nfkbil2 complex is crucial for maintaining genome stability during DNA replication. Its loss leads to genomic instability and DNA damage, highlighting its role in regulating stalled replication forks.

Area of Science:

  • Cellular biology
  • Molecular genetics
  • Genomics

Background:

  • Cullin 4 (Cul4)-based ubiquitin ligases are key regulators of DNA replication and repair.
  • Over 50 Cul4-specific adaptors (DCAFs) form distinct Cul4 complexes.

Purpose of the Study:

  • To analyze the function of DCAFs and Cul4-linked proteins in cell cycle progression.
  • To identify novel factors involved in maintaining genome stability.

Main Methods:

  • Live-cell imaging-based RNAi screen to assess DCAF and Cul4-linked protein function.
  • Investigated the role of C6orf167/Mms22-like protein (Mms22L) in human cells.
  • Analyzed the interaction between Mms22L and Nfkbil2.

Main Results:

  • Identified specific Cul4-associated factors required for G1 and S phase progression.
  • Discovered Mms22L as a human protein regulating genome stability by promoting replication through difficult DNA regions.
  • Loss of Mms22L causes S phase-dependent genomic instability, including double-strand breaks and checkpoint activation.
  • Mms22L is degraded in a Cul4-dependent manner upon replication stress.
  • Mms22L interacts with Nfkbil2, which is associated with chromatin and DNA replication/repair factors.

Conclusions:

  • The Mms22L-Nfkbil2 complex is essential for maintaining genome stability.
  • This complex regulates the chromatin state at stalled replication forks, preventing DNA damage.
  • Mms22L's function is conserved but distinct from its yeast ortholog Mms22, particularly in its interaction with Cul4.

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