Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1

ABSTRACT: Telomeres play crucial roles during tumorigenesis inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alters telomeric chromatin composition and function. Here we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveals upregulation of proteins involved in chromatin remodeling, DNA repair and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Romain Hamelin  

LAB HEAD: Joachim Lingner

PROVIDER: PXD010088 | Pride | 2018-07-13

REPOSITORIES: Pride