RTEL-1 and DNA polymerase theta promote subtelomeric DNA synthesis and telomere fusion in C. elegans

Abstract

AbstractInterstitial telomere sequences (ITS) are degenerate telomere tracts scattered along chromosome arms whose functions are not well understood. We found that critically shortened telomeres of C. elegans telomerase mutants initiate DNA synthesis within ITS tracts that were close to or far from a telomere. Some ITS tracts were targeted recurrently. RTEL-1 dismantles T-loops and recombination intermediates, and DNA polymerase theta (POLQ-1) promotes end-joining using short segments of microhomology. In telomerase mutants, RTEL-1 and POLQ-1 promoted telomere fusion and DNA synthesis at subtelomeric ITS tracts. RTEL-1 is known to suppress homologous recombination, and we found that RTEL-1 similarly suppressed POLQ-1-mediated double-strand break repair. Mutation signatures characteristic of repair by POLQ-1 occurred during initiation of subtelomeric DNA synthesis and at subsequent template shifting events. We propose that RTEL-1 and POLQ-1 play distinct essential roles in subtelomeric DNA synthesis, a process that may contribute significantly to telomere fusion and tumor genome evolution.