Abstract

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by the premature onset of a number of age-related diseases, including cancers. The gene responsible for WS (WRN in human or Wrn in mouse) encodes a DNA helicase/exonuclease protein. Participation in a replication complex is among the several functions postulated for the Wrn protein [reviewed in 1]. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, which is known to bind to DNA damage, is also associated with the DNA replication complex [2]. To determine if Wrn and PARP-1 enzymes act in concert during cell growth, mice with a mutation in the helicase domain of the Wrn gene (WrnDhel/Dhel mice) were crossed to PARP-1 null mice. Phenotypically, double mutant mice (PARP-1 null/WrnDhel/Dhel) developed tumors more rapidly than Wrn mutants. At the cellular levels, mouse embryonic fibroblasts derived from such PARP-1 null/WrnDhel/Dhel mice stop dividing abruptly unlike WrnDhel/Dhel or PARP-1 null cells. At the chromosomal level, PARP-1 null/WrnDhel/Dhel fibroblasts were distinguished by an increased frequency of chromatid breaks, chromosome rearrangements, and fragmentation. Interestingly, different sets of genes are rearranged in PARP-1 null/WrnDhel/Dhel cells compared to PARP-1 null or WrnDhel/Dhel cells. Finally, experiments have indicated that PARP-1 co-immunoprecipitate with the human WRN protein. These results suggest that WRN (or Wrn in mouse) and PARP-1 enzymes may be part of a complex involved in the processing of DNA breaks. References: 1.Lebel M: Werner syndrome: genetic and molecular basis of a premature aging disorder. Cell Mol Life Sci, 2001; 58: 857-867 2.Simbulan-Rosenthal CM, Rosenthal DS, Hilz H et al: The expression of poly(ADP-ribose) polymerase during differentiation-linked DNA replication reveals that it is a component of the multiprotein DNA replication complex. Biochemistry, 1996; 35: 11622-11633

Keywords: Werner’s syndrome, PARP-1, genomic instability, senescence, tumor progression