Tag Archives: Werner Syndrome

WRN RQC

Ken Kitano and colleagues have co-crystallised the RecQ C-terminal (RQC) domain of human WRN bound to a DNA duplex. In their recent Structure paper, they describe how the RQC domain interacts with a blunt end of the duplex and, surprisingly, unpairs a Watson-Crick base pair in the absence of an ATPase domain. The β wing, an extended hairpin motif characteristic of winged-helix motifs, is used as a “separating knife” to wedge between the first and second base pair. However, the recognition helix, a component of helix-turn-helix motifs embedded within DNA grooves, is excluded from the interaction.

These results present a function of the winged-helix motif central to the helicase reaction, and add further paradigmatic insights on the structural biology of RecQ helicases.

doi:10.1016/j.str.2009.12.011

Structural Basis for DNA Strand Separation by the Unconventional Winged-Helix Domain of RecQ Helicase WRN

by

Ken Kitano,  Sun-Young Kim, and Toshio Hakoshima

Volume 18, Issue 2, 10 February 2010, Pages 177-187

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Filed under ageing, aging, RecQ, structural biology, Werner Syndrome, WRN

introduction of a normal human chromosome 8 corrects Werner Syndrome cells

Kentaro Ariyoshi and colleagues successfully introduced a normal human chromosome 8 into Werner Syndrome (WS) cells(fibroblasts) immortalized by expressing a human telomere reverse transcriptase subunit (hTERT) gene. In their study (published in the Journal of Radiation Research), they demonstrated that the abnormal WS cellular phenotypes like sensitivity to 4-nitroquinoline-1-oxide (4NQO) and hydroxyurea (HU), and chromosomal radiosensitivity at G(2) phase can be corrected by expression of the WRN gene upon introduction of a chromosome 8 via microcell fusion. Their results provide more evidence that the multiple abnormal WS phenotypes (clinical, cellular, and chromosomal) are derived from a primary, but not secondary, defect in the WRN gene.

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Filed under progeria, progeroid syndrome, Werner Syndrome, Werners Syndrome, WRN, WS

WRN and MUS81

There is a Journal of Cell Biology paper by Annapaola Franchitto and colleagues entitled:

Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway

Below is tha abstract:

Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.

Published online October 13, 2008
doi:10.1083/jcb.200803173
The Journal of Cell Biology, Vol. 183, No. 2, 241-252


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Filed under ageing, biogerontology, cell biology, DNA, DNA damage, DNA repair, double strand break, endonuclease, genetics, recombination, replication, Werner Syndrome, Werners Syndrome