DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects

Abstract

DDX11 encodes an iron–sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug–resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.

Vertebrate CTF18 and DDX11 essential function in cohesion is bypassed by preventing WAPL-mediated cohesin release

“…Here we started out by investigating the functions of CTF18-RFC versus DDX11, both associated with DNA repair and implicated in human disease ( Gellon et al 2011 ; Price et al 2013 ; Abe et al 2018b ; van Schie et al 2020 ; Jegadesan and Branzei 2021 ). We found that in avian DT40 cells, CTF18 loss causes negligible defects, but combined deficiency in CTF18 and DDX11 genes causes synthetic lethality due to severely compromised SCC and chromosome missegregation.…”

The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

“…Chl1/DDX11 —Mutations in DDX11 underlie the cohesinopathy Warsaw breakage syndrome [ 132 , 133 ]. DDX11 deficiency sensitizes to various types of DNA damage including PARP-inhibition, G4-stabilization, UV, cisplatin, ATR inhibition, and Topoisomerase inhibition [ 84 , 110 , 134 , 135 ]. DDX11 facilitates DNA replication, fork restart, and the processing of G4 structures [ 84 , 125 , 130 ].…”

“…DDX11 facilitates DNA replication, fork restart, and the processing of G4 structures [ 84 , 125 , 130 ]. In response to DNA damage, Chl1/DDX11 promotes the formation of ssDNA as a suitable substrate for RPA loading, thereby contributing to efficient CHK1 activation, RAD51-dependent HR, and cohesin loading on stalled replication forks [ 58 , 85 , 135 ]. All functions of Chl1/DDX11 in DNA replication and repair depend on its helicase function [ 58 , 82 , 84 , 135 ].…”

“…In response to DNA damage, Chl1/DDX11 promotes the formation of ssDNA as a suitable substrate for RPA loading, thereby contributing to efficient CHK1 activation, RAD51-dependent HR, and cohesin loading on stalled replication forks [ 58 , 85 , 135 ]. All functions of Chl1/DDX11 in DNA replication and repair depend on its helicase function [ 58 , 82 , 84 , 135 ]. In contrast, while the interaction of DDX11 with TIMELESS is important for efficient replication in response to HU and the processing of G4 structures [ 125 , 130 ], CPT and PARPi resistance are independent of this interaction [ 135 ].…”

“…All functions of Chl1/DDX11 in DNA replication and repair depend on its helicase function [ 58 , 82 , 84 , 135 ]. In contrast, while the interaction of DDX11 with TIMELESS is important for efficient replication in response to HU and the processing of G4 structures [ 125 , 130 ], CPT and PARPi resistance are independent of this interaction [ 135 ]. In yeast, the interaction with Ctf4 is dispensable for HU resistance and RPA/cohesin loading at stalled forks [ 58 , 82 ].…”