A lack of telomeric non-reciprocal recombination (TENOR) may account for the premature proliferation blockade of Werner's syndrome fibroblasts.
Cell lineages survive as long as their descendants replicate. In human diploid fibroblasts (HDF) there is a telomere-driven clock that determines the limited replicative life span of their cell branches. Werner's syndrome fibroblasts (WF) prematurely limit their replicative life span compared to HDF on account of a defective RecQ helicase, WRNp. Here, we introduce the concept of telomeric non-reciprocal recombination (TENOR) and suggest that its dysregulation in WF is responsible for their premature senescence. We postulate that TENOR functions at the level of four-strand replisomes which are specific for and initiated at fused chromosome ends. Consequently, healthy replicatively senescent fibroblasts can undergo one further division mediated by a TENOR event. Thereby, one of the two daughter cells re-acquires proliferation capacity that initiates a new proliferating cell branch from the formerly replicatively senescent cell. We argue that the unique mechanisms of action of WRNp support this concept, and we apply it to WF. If it is stipulated that WF are defective for TENOR because of their defective WRNp, a simple model emerges as to how they become prematurely senescent.
Hasenmaile
Stefan
S
Tübingen Ageing and Tumour Immunology Group, Section for Transplantation Immunology and Immunohaematology, Zentrum für Medizinische Forschung, University of Tübingen, 72072 Tübingen, Germany. stefan_hasenmaile@yahoo.de
Pawelec
Graham
G
Wagner
Wolfgang
W
D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage; D016922:Cellular Senescence / Q000502:physiology; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D053484:RecQ Helicases; D011995:Recombination, Genetic; D016615:Telomere / Q000378:metabolism*; D014898:Werner Syndrome / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase