Molecular mechanisms of proliferative senescence and genomic instability in Werner syndrome and the WRN gene network

Background: Ageing is a general, intrinsic and progressively deleterious process that affects all cells, tissues and organs albeit at different extent and rate in each individual. The complexity and universality of its phenotypic manifestations suggest a multifactorial origin. The autosomal recessive disorder Werner syndrome likely represents a segmental progeroid disorder since patients show several, but not all phenotypes of premature ageing. Summary: Proliferative senescence of diploid cells in culture provided a model system in which ageing can be studied experimentally. Cultures of cells from patients with Werner syndrome experienced an extreme form of proliferative senescence and a clonal succession of translocations, known as variegated translocation mosaicism. In addition, Werner syndrome cells showed spontaneous deletion formation and a prolongation of and arrest in the S phase of the cell cycle. The WRN protein harbors a helicase, an exonuclease and a RecQ interaction domain. With the latter the WRN protein may interact with NBS1, RPA, MRE11, TREX1, MUTYH, POT1, TRF1, FEN-1, PAPRP-1, p97/VCP, TRF2, DNA polymerase(beta), Ku76/80, EXO-1, NEIL1, and p53, which are key to DNA damage response pathways including canonical NHEJ, homologous recombination, base excision repair and telomere maintenance. The WRN exonuclease domain is a target of WRNIP1 binding, which links WRN to resolution of stalled replication due to collision with transcription and the ATM-mediated cell cycle checkpoint. . Patients with an incomplete complement of Werner syndrome phenotypes, called atypical Werner syndrome patients, were found to carry variants in LMNA, POLD1, SPRTN, MDM2, CTC1, SAMHD1. Key messages: These findings broaden the genotypic landscape and the phenotypic spectrum of Werner syndrome. In this review potential molecular mechanisms underlying genomic instability in Werner syndrome, including chromothripsis due to asynchronous S phase traverse and telomere crises followed by bridge fusion breakage cycles are discussed. The participation of WRN in multiple gene networks is consistent with the multifactorial nature of ageing in general.