| First Author | Lebel M | Year | 2003 |
| Journal | Am J Pathol | Volume | 162 |
| Issue | 5 | Pages | 1559-69 |
| PubMed ID | 12707040 | Mgi Jnum | J:83068 |
| Mgi Id | MGI:2656673 | Doi | 10.1016/S0002-9440(10)64290-3 |
| Citation | Lebel M, et al. (2003) Genetic Cooperation between the Werner Syndrome Protein and Poly(ADP-Ribose) Polymerase-1 in Preventing Chromatid Breaks, Complex Chromosomal Rearrangements, and Cancer in Mice. Am J Pathol 162(5):1559-69 |
| abstractText | Werner syndrome is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for Werner syndrome encodes a DNA helicase/exonuclease protein. Participation in a replication complex is among the several functions postulated for the WRN protein. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, which is known to bind to DNA strand breaks, is also associated with the DNA replication complex. To determine whether Wrn and PARP-1 enzymes act in concert during cell growth, mice with a mutation in the helicase domain of the Wrn gene (Wrn(Deltahel/Deltahel) mice) were crossed to PARP-1-null mice. Both Wrn(Deltahel/Deltahel) and PARP-1-null/Wrn(Deltahel/Deltahel) cohorts developed more neoplasms than wild-type animals. The tumor spectrum was the same between PARP-1-null/Wrn(Deltahel/Deltahel) mice and Wrn mutants. However, PARP-1-null/Wrn(Deltahel/Deltahel) mice developed neoplasms at a younger age. Mouse embryonic fibroblasts derived from such PARP-1-null/Wrn(Deltahel/Deltahel) mice stop dividing abruptly unlike Wrn(Deltahel/Deltahel) or PARP-1-null cells. PARP-1-null/Wrn(Deltahel/Deltahel) fibroblasts were distinguished by an increased frequency of chromatid breaks, complex chromosomal rearrangements, and fragmentation. Finally, experiments have indicated that the PARP-1 enzyme co-immunoprecipitates with the WRN protein in human 293 embryonic kidney cells. These results suggest that Wrn and PARP-1 enzymes may be part of a complex involved in the processing of DNA breaks. |
