Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase

Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19357-62. doi: 10.1073/pnas.1210304109. Epub 2012 Nov 5.

Abstract

Bloom syndrome (BS) is an autosomal recessive disorder caused by mutations in the RecQ-like DNA helicase BLM, which functions in the maintenance of genome stability. Using a humanized model of Saccharomyces cerevisiae that expresses a chimera of the N terminus of yeast Sgs1 and the C terminus of human BLM from the chromosomal SGS1 locus, we have functionally evaluated 27 BLM alleles that are not currently known to be associated with BS. We identified nine alleles with impaired function when assessed for hypersensitivity to the DNA-damaging agent hydroxyurea (HU). Six of these alleles (P690L, R717T, W803R, Y811C, F857L, G972V) caused sensitivity to HU that was comparable to known BS-associated or helicase-dead alleles, suggesting that they may cause BS and, in the heterozygous state, act as risk factors for cancerogenesis. We also identified three alleles (R791C, P868L, G1120R) that caused intermediate sensitivity to HU; although unlikely to cause BS, these partial loss-of-function alleles may increase risk for cancers or other BS-associated complications if a person is homozygous or compound heterozygous for these alleles or if they carry a known BS-associated allele.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Amino Acids / genetics
  • Bloom Syndrome / enzymology*
  • Bloom Syndrome / genetics*
  • Diploidy
  • Heterozygote
  • Homozygote
  • Humans
  • Hydroxyurea / pharmacology
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • RecQ Helicases / chemistry
  • RecQ Helicases / genetics*
  • RecQ Helicases / metabolism
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics

Substances

  • Amino Acids
  • Mutant Proteins
  • Saccharomyces cerevisiae Proteins
  • Bloom syndrome protein
  • SGS1 protein, S cerevisiae
  • RecQ Helicases
  • Hydroxyurea