Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells

Abstract

AbstractThe WRN RECQ helicase is responsible for the Werner syndrome of premature aging and cancer predisposition. Substantial progress has been made in delineating WRN functions in multiple aspects of DNA metabolism, including DNA replication, repair, transcription, and telomere maintenance. Nevertheless, a complete mechanistic understanding of how loss of WRN accelerates aging in humans has not been achieved yet. Here we show that WRN is involved in the maintenance of constitutive heterochromatin, CH, in proliferating, immortalized human fibroblasts. WRN is found within a complex with histone deacetylase 2, HDAC2, and WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1α. WRN deficiency derepresses SATII pericentromeric satellite repeats and reduces a subset of protein-protein interactions that participate in the organization of CH in the nucleus. In particular, WRN deficiency reduces the complexes involving Lamin B1 and Lamin B receptor, LBR. Both mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and the latter phenotype does not require WRN catalytic activities. At the mRNA level, WRN supports complete maturation of the LBR mRNA. All signs of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence, and WRN complexes with HP1α and HDAC2 are also markedly downregulated in these senescing cells. The data suggest that WRN loss affects heterochromatin independently of the senescence program but can mimic aspects of it and thus sensitize cells to triggers of senescence.