RAD54L2 counters TOP2-DNA adducts to promote genome stability (Etoposide treated RPE1 CRISPR screens in TP53 and RAD53L2 knock outs)

The catalytic cycle of topoisomerase 2 (TOP2) enzymes proceeds via a
transient DNA double-strand break (DSB) intermediate termed the TOP2
cleavage complex (TOP2cc), in which the TOP2 protein is covalently bound
to DNA. Anti-cancer agents such as etoposide operate by stabilising
TOP2ccs, ultimately generating genotoxic TOP2-DNA protein crosslinks that
require processing and repair. Here, we identify RAD54-like 2 (RAD54L2) as
a factor promoting TOP2cc resolution. We demonstrate that RAD54L2 acts
through a novel mechanism together with zinc finger protein associated
with TDP2 and TOP2 (ZATT/ZNF451) and independent of tyrosyl-DNA
phosphodiesterase 2 (TDP2). Our work suggests a model wherein RAD54L2
recognises sumoylated-TOP2 and, using its ATPase activity, promotes TOP2cc
resolution and prevents DSB exposure. These findings suggest
RAD54L2-mediated TOP2cc resolution as a potential mechanism for
cancer-therapy resistance and highlight RAD54L2 as an attractive candidate
for drug discovery.