A mechanism for telomere-specific telomere length regulation

Abstract

Telomere length is a critical determinant of telomere function and hence chromosome stability. Critically short telomeres induce cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases. Conversely, maintenance of telomere length is a hallmark of cancer. How telomere set-length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here we detail a mechanism of a telomere-specific set-length regulation that causes drastic differences in telomere length between individual telomeres in the same cell. Indeed, the results show that telomerase recruitment is modulated in cis in a telomere-specific way. Increased Sir4 abundance on yeast TEL03L subtelomeric heterochromatin leads to a set-length maintenance that is two to three times higher than on any other telomere. Remarkably, the distal 15 kb of TEL03L are sufficient to transfer this telomere specific set-length regulation to another chromosome. Furthermore, a mutation in the telomere boundary element protein Tbf1 allows increased Sir4 binding on all telomeres and hence results in longer set-lengths. The results therefore will force a rethinking of telomere length regulation away from the generalized view that all telomeres are treated the same to a more telomere-specific treatment. HIGHLIGHTSO_LIRegulation of the set-length of telomeric repeats is telomere-specific. C_LIO_LITEL03L on yeast chromosome III displays a set-length regulation that confers an extremely long repeat tract. C_LIO_LITransferring the distal part of TEL03L onto chromosome XV is sufficient to impose the very long set-length regulation. C_LIO_LITelomere-specific tract set-length regulation depends on the alternate telomerase recruitment pathway involving Sir4 and yKU and the chromatin boundary protein Tbf1. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/598646v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1c3bb52org.highwire.dtl.DTLVardef@13f338forg.highwire.dtl.DTLVardef@51f91aorg.highwire.dtl.DTLVardef@1b95ac0_HPS_FORMAT_FIGEXP M_FIG C_FIG