MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability

Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11485-90. doi: 10.1073/pnas.0601828103. Epub 2006 Jul 24.

Abstract

Spindle assembly checkpoint (SAC) ensures bipolar attachment of chromosomes to the mitotic spindle and is essential for faithful chromosome segregation, thereby preventing chromosome instability (CIN). Genetic evidence suggests a causal link between compromised SAC, CIN, and cancer. Bloom syndrome (BS) is a genetic disorder that predisposes affected individuals to cancer. BS cells exhibit elevated rates of sister chromatid exchange, chromosome breaks, and CIN. The BS gene product, BLM, is a member of the RecQ helicases that are required for maintenance of genome stability. The BLM helicase interacts with proteins involved in DNA replication, recombination, and repair and is required for the repair of stalled-replication forks and in the DNA damage response. Here we present biochemical evidence to suggest a role of BLM phosphorylation during mitosis in maintaining chromosome stability. BLM is associated with the SAC kinase MPS1 and is phosphorylated at S144 in a MPS1-dependent manner. Phosphorylated BLM interacts with polo-like kinase 1, a mitotic kinase that binds to phosphoserine/threonine through its polo-box domain (PBD). Furthermore, BS cells expressing BLM-S144A show normal levels of sister chromatid exchange but fail to maintain the mitotic arrest when SAC is activated and exhibit a broad distribution of chromosome numbers. We propose that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Antineoplastic Agents / metabolism
  • Bloom Syndrome / genetics
  • Bloom Syndrome / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Chromosomal Instability*
  • Chromosome Segregation
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Mitosis / physiology*
  • Nocodazole / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RecQ Helicases
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sister Chromatid Exchange
  • Spindle Apparatus / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • TTK protein, human
  • Adenosine Triphosphatases
  • Bloom syndrome protein
  • DNA Helicases
  • RecQ Helicases
  • Nocodazole