RAD54 promotes alternative lengthening of telomeres by mediating branch migration

Abstract

Cancer cells can activate the alternative lengthening of telomeres (ALT) pathway to promote replicative immortality. The ALT path- way promotes telomere elongation through a homologous recom- bination pathway known as break-induced replication (BIR), which is often engaged to repair single-ended double-stranded breaks (DSBs). Single-ended DSBs are resected to promote strand invasion and facilitate the formation of a local displacement loop (D-loop), which can trigger DNA synthesis, and ultimately promote telomere elongation. However, the exact proteins involved in the matura- tion, migration, and resolution of D-loops at ALT telomeres are unclear. In vitro, the DNA translocase RAD54 both binds D-loops and promotes branch migration suggesting that RAD54 may func- tion to promote ALT activity. Here, we demonstrate that RAD54 is enriched at ALT telomeres and promotes telomeric DNA synthesis through its ATPase-dependent branch migration activity. Loss of RAD54 leads to the formation of unresolved recombination inter- mediates at telomeres that form ultra-fine anaphase bridges in mitosis. These data demonstrate an important role for RAD54 in promoting ALT-mediated telomere synthesis.