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The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis
Monique F. Smeets, … , David J. Izon, Carl R. Walkley
Monique F. Smeets, … , David J. Izon, Carl R. Walkley
Published June 24, 2014
Citation Information: J Clin Invest. 2014;124(8):3551-3565. https://doi.org/10.1172/JCI75334.
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Research Article Hematology Article has an altmetric score of 2

The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis

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Abstract

Mutations within the gene encoding the DNA helicase RECQL4 underlie the autosomal recessive cancer-predisposition disorder Rothmund-Thomson syndrome, though it is unclear how these mutations lead to disease. Here, we demonstrated that somatic deletion of Recql4 causes a rapid bone marrow failure in mice that involves cells from across the myeloid, lymphoid, and, most profoundly, erythroid lineages. Apoptosis was markedly elevated in multipotent progenitors lacking RECQL4 compared with WT cells. While the stem cell compartment was relatively spared in RECQL4-deficent mice, HSCs from these animals were not transplantable and even selected against. The requirement for RECQL4 was intrinsic in hematopoietic cells, and loss of RECQL4 in these cells was associated with increased replicative DNA damage and failed cell-cycle progression. Concurrent deletion of p53, which rescues loss of function in animals lacking the related helicase BLM, did not rescue BM phenotypes in RECQL4-deficient animals. In contrast, hematopoietic defects in cells from Recql4Δ/Δ mice were fully rescued by a RECQL4 variant without RecQ helicase activity, demonstrating that RECQL4 maintains hematopoiesis independently of helicase activity. Together, our data indicate that RECQL4 participates in DNA replication rather than genome stability and identify RECQL4 as a regulator of hematopoiesis with a nonredundant role compared with other RecQ helicases.

Authors

Monique F. Smeets, Elisabetta DeLuca, Meaghan Wall, Julie M. Quach, Alistair M. Chalk, Andrew J. Deans, Jörg Heierhorst, Louise E. Purton, David J. Izon, Carl R. Walkley

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Figure 10

The RecQ DNA helicase function of RECQL4 is not required for hematopoiesis.

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The RecQ DNA helicase function of RECQL4 is not required for hematopoies...
(A) Outline of experimental design and constructs tested for rescue. (B) Genomic PCR from cells of each population treated for 5 days with tamoxifen, demonstrating efficient gene deletion, and CFU assays counted at day 7 from each population with tamoxifen added to the methylcellulose. (C) Analysis of the rescue of colony formation in cells of the indicated genotypes infected either with WT or K508A helicase defective RECQL4; GFP–ve cells were included as a control. (D) Fold change in GFP levels and representative FACS plots relative to initial transduction levels over 21 days of culture for cells of the indicated genotypes. (E) B cell development is normalized by the K508A mutant. (F) Rescue of T cell development by helicase defective RECQL4. Data expressed as mean ± SEM, Student’s t test. n = 4 per genotype. Experiments were independently performed on 2 separate occasions with results pooled for presentation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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