Mutator phenotype of Werner syndrome is characterized by extensive deletions.

Abstract

Werner syndrome (WS) is a rare autosomalrecessive disorder characterized by the premature appearance of features of normal aging in young adults. The extensive phenotypic overlap between WS and normal aging suggests they may also share pathogenetic mechanisms. We reported previously that somatic cells from WS patients demonstrate a

Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

“…This observation is consistent with the possibility that in the absence of active WRN the spontaneous damage at the replication fork cannot be resolved properly, leading to recruitment of HR molecular apparatus. In addition, persistence of DNA strand breaks in WS cells could be consistent with the observed higher rate of DNA rearrangements (Gebhart et al, 1988;Fukuchi et al, 1989). Furthermore, a possible consequence of this higher yield of DNA strand breaks is that the effect of the reported interruption of RNA synthesis by CPT, which results in an SSB in the transcribed strand (Barrows et al, 1998;Mosesso et al, 2000), combined with one gap in the other strand, could lead to cytotoxic DSB in G2 cells, thus resulting in cell death.…”

“…This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. One of the hallmarks of WS patients is the genomic instability as evidenced by the spontaneous chromosome anomalies and large deletions in many genes (Salk et al, 1985;Fukuchi et al, 1989). It has been demonstrated that WRN exhibits DNA unwinding activity (Gray et al, 1997;Suzuki et al, 1997) and exonuclease activity residing in the N-terminal region (Huang et al, 1998).…”

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

“…77,78 This impairment could derive from the inability of cells to resolve fork stalling in the absence of WRN resulting in degeneration into DSBs, thus requiring engagement of HR. This is in agreement with the characteristic high rate of recombination of WS cells 56,89 and our observation that RAD51 depletion affects viability of WS cells after prolonged replication arrest (Franchitto A and Pichierri P, unpublished).…”

Bloom's syndrome gene suppresses premature ageing caused by Sgs1 deficiency in yeast

“…Cultured cells derived from patients with WS show an increased rate of somatic mutations, chromosome losses, and deletions Fukuchi et al 1989;Monnat et al 1992). Increased rates of sister chromatid exchange and chromosomal aberration have been observed in cells having defects in the BLM gene (Langlois et al 1989).…”