Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome

Cell Mol Life Sci. 2014 Jul;71(14):2625-39. doi: 10.1007/s00018-014-1569-4. Epub 2014 Feb 1.

Abstract

In 2010, a new recessive cohesinopathy disorder, designated Warsaw breakage syndrome (WABS), was described. The individual with WABS displayed microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Cytogenetic analysis revealed mitomycin C (MMC)-induced chromosomal breakage; however, an additional sister chromatid cohesion defect was also observed. WABS is genetically linked to bi-allelic mutations in the ChlR1/DDX11 gene which encodes a protein of the conserved family of Iron-Sulfur (Fe-S) cluster DNA helicases. Mutations in the budding yeast ortholog of ChlR1, known as Chl1, were known to cause sister chromatid cohesion defects, indicating a conserved function of the gene. In 2012, three affected siblings were identified with similar symptoms to the original WABS case, and found to have a homozygous mutation in the conserved Fe-S domain of ChlR1, confirming the genetic linkage. Significantly, the clinically relevant mutations perturbed ChlR1 DNA unwinding activity. In addition to its genetic importance in human disease, ChlR1 is implicated in papillomavirus genome maintenance and cancer. Although its precise functions in genome homeostasis are still not well understood, ongoing molecular studies of ChlR1 suggest the helicase plays a critically important role in cellular replication and/or DNA repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abnormalities, Multiple / genetics*
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / physiology
  • DNA Breaks
  • DNA Helicases / genetics*
  • DNA Helicases / physiology
  • G-Quadruplexes
  • Genomic Instability
  • Homeostasis
  • Humans
  • Mitomycin
  • Mutation
  • Neoplasms / genetics
  • Papillomaviridae / genetics
  • Phenotype
  • Substrate Specificity
  • Syndrome

Substances

  • Mitomycin
  • DNA Helicases
  • DDX11 protein, human
  • DEAD-box RNA Helicases