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

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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.

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Acknowledgments

This work is funded in part by the National Institutes of Health (NIH) and the National Institute on Aging (NIA) (R.M.B.), and by the Saskatchewan Health Research Foundation (SHRF) and the Natural Sciences and Engineering Research Council of Canada (NSERC) (Y.W.). We thank Drs. H. Vallabhaneni and J. Yin (NIA–NIH) for critically reading the manuscript. We wish to dedicate this paper to the memory of Dr. Johan P. de Winter, an outstanding scientist who led efforts in understanding the molecular-genetic basis of Warsaw breakage syndrome, Fanconi anemia, and other genetic disorders.

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  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, MD, 21224, USA

    Sanjay Kumar Bharti, Irfan Khan, Taraswi Banerjee, Joshua A. Sommers & Robert M. Brosh Jr.

  2. Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada

    Yuliang Wu

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  1. Sanjay Kumar Bharti
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  2. Irfan Khan
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Correspondence to Robert M. Brosh Jr..

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Bharti, S.K., Khan, I., Banerjee, T. et al. Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome. Cell. Mol. Life Sci. 71, 2625–2639 (2014). https://doi.org/10.1007/s00018-014-1569-4

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  • DOI: https://doi.org/10.1007/s00018-014-1569-4

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