RAD54L2-Mediated DNA Damage Avoidance Pathway Specifically Preserves Genome Integrity in Response to Topoisomerase 2 Poisons

Authors

Huimin Zhang
Yun Xiong
Yilun Sun
Jeong-Min Park
Dan Su
Xu Feng
Sarah Keast
Mengfan Tang
Min Huang
Chao Wang
Mrinal Srivastava
Chang Yang
Dandan Zhu
Zhen Chen
Siting Li
Ling Yin
Yves Pommier
Junjie Chen

Publication Date

12-8-2023

Journal

Science Advances

Abstract

Type II topoisomerases (TOP2) form transient TOP2 cleavage complexes (TOP2ccs) during their catalytic cycle to relieve topological stress. TOP2ccs are covalently linked TOP2-DNA intermediates that are reversible but can be trapped by TOP2 poisons. Trapped TOP2ccs block transactions on DNA and generate genotoxic stress, which are the mechanisms of action of TOP2 poisons. How cells avoid TOP2cc accumulation remains largely unknown. In this study, we uncovered RAD54 like 2 (RAD54L2) as a key factor that mediates a TOP2-specific DNA damage avoidance pathway. RAD54L2 deficiency conferred unique sensitivity to treatment with TOP2 poisons. RAD54L2 interacted with TOP2A/TOP2B and ZATT/ZNF451 and promoted the turnover of TOP2 from DNA with or without TOP2 poisons. Additionally, inhibition of proteasome activity enhanced the chromatin binding of RAD54L2, which in turn led to the removal of TOP2 from chromatin. In conclusion, we propose that RAD54L2-mediated TOP2 turnover is critically important for the avoidance of potential TOP2-linked DNA damage under physiological conditions and in response to TOP2 poisons.

Keywords

Poisons, DNA Topoisomerases, Type II, DNA Damage, DNA Repair, DNA, Chromatin

DOI

10.1126/sciadv.adi6681

PMID

38055811

PMCID

PMC10699775

PubMedCentral® Posted Date

12-6-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes