Abstract
Cancer cells can activate the alternative lengthening of telomeres (ALT) pathway to promote replicative immortality. The ALT pathway promotes telomere elongation through a homologous recombination 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 maturation, 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 function 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 intermediates at telomeres that form ultra‐fine anaphase bridges in mitosis. These data demonstrate an important role for RAD54 in promoting ALT‐mediated telomere synthesis.
Highlights
Cancer cells must maintain telomere length in order to escape crisis and overcome cellular senescence
These findings suggest that RAD54 regulates the formation and resolution of recombination intermediates, but that RAD54 may ensure the fidelity of homologous recombination by regulating heterologous strand invasion events
Given the crucial role of RAD54 in homology-directed repair processes in eukaryotic cells, we asked whether RAD54 functions at alternative lengthening of telomere (ALT) telomeres to promote break-induced replication
Summary
Cancer cells must maintain telomere length in order to escape crisis and overcome cellular senescence. Following the initiation of DNA synthesis, the POLD3 subunit of Pold replaces Polg and synthesizes longer tracts of DNA to promote telomere extension events [6,17] These extended D-loops must be processed to resolve the joint molecules and ensure completion of telomere elongation. During pre-synapsis, a broken DNA end is resected to form a 30 single-stranded overhang This overhang is bound by RAD51 to create a nucleoprotein filament that promotes strand invasion during the search for a homologous template. RAD54 can dissolve a Dloop that has formed with mismatches between the invading strand and template DNA [36] Together, these findings suggest that RAD54 regulates the formation and resolution of recombination intermediates, but that RAD54 may ensure the fidelity of homologous recombination by regulating heterologous strand invasion events. Our data highlight a post-synaptic function for RAD54 during the dissolution of recombination intermediates at ALT telomeres
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