2. Academic Validation
  3. RAD54L2 counters TOP2-DNA adducts to promote genome stability

RAD54L2 counters TOP2-DNA adducts to promote genome stability

  • Sci Adv. 2023 Dec 8;9(49):eadl2108. doi: 10.1126/sciadv.adl2108.
Giuseppina D'Alessandro 1 2,  David A Morales-Juarez 2,  Sean L Richards 1 2,  Karin C Nitiss 3,  Almudena Serrano-Benitez 1 2,  Juanjuan Wang 4,  John C Thomas 2,  Vipul Gupta 2,  Andrea Voigt 1 2,  Rimma Belotserkovskaya 1 2,  Chen Gang Goh 1 2,  Anne Ramsay Bowden 2,  Yaron Galanty 1 2,  Petra Beli 4 5,  John L Nitiss 3,  Guido Zagnoli-Vieira 2,  Stephen P Jackson 1 2
Affiliations

Affiliations

  • 1 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 2 The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 3 UIC College of Pharmacy, Rockford, IL, USA.
  • 4 Institute of Molecular Biology (IMB), Chromatin Biology & Proteomics, Mainz, Germany.
  • 5 Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany.
PMID: 38055822 DOI: 10.1126/sciadv.adl2108
Abstract

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. Anticancer agents such as etoposide operate by stabilizing TOP2ccs, ultimately generating genotoxic TOP2-DNA protein cross-links 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 tyrosyl-DNA phosphodiesterase 2 (TDP2) and TOP2 (ZATT/ZNF451) and independent of TDP2. Our work suggests a model wherein RAD54L2 recognizes 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z