ERCC1-XPF deficiency is a predictor of olaparib induced synthetic lethality and platinum sensitivity in epithelial ovarian cancers

Mesquita, Katia A.; Alabdullah, Muslim; Griffin, Michaela; Toss, Michael S.; Fatah, Tarek M.A. Abdel; Alblihy, Adel; Moseley, Paul M.; Chan, Sy; Rakha, Emad A.; Madhusudan, Srinivasan

doi:10.1016/j.ygyno.2019.02.014

Cited by 33 publications

(28 citation statements)

References 23 publications

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“…Finally, there is a pressing need to explore chemical inhibition of XPF-ERCC1 to sensitise cancer cells to platinum-based therapeutics and reduce drug resistance mediated by XPF-ERCC1. Equally, XPF-ERCC1 inhibitors could target cancer cell vulnerabilities including XPF-FANCM synthetic lethality relevant to FANCM-deficient tumours 44 and potentially other platinumsensitive contexts 45 . The availability of an atomic structure for human XPF-ERCC1 described here will encourage efforts to develop new precision medicines as well as to overcome cancer chemoresistance 46 .…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

et al. 2020

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“…Interestingly, however, in vitro data demonstrates that NER alteration does not confer sensitivity to PARPi, suggesting that PARP and platinum sensitivity do not always occur in parallel [48]. ERCC1 and XPF are the two components of NER that are potentially most important for removal of platinum-DNA adducts [49]. ERCC1 complexed with XPF is involved in the 5 cleavage of DNA strands that carry platinum adduct.…”

Section: Nucleotide Excision Repairmentioning

confidence: 99%

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

McMullen

Karakasis

Madariaga

et al. 2020

Cancers

124

115

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Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.

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“…There is a pressing need to explore opportunities for chemical inhibition of XPF-ERCC1 in view of the XPF synthetic lethality with the DNA translocase FANCM, particularly relevant to FANCM-deficient tumours 44 and also with PARP inhibition 45 . The availability of an atomic structure for human XPF-ERCC1 described here will encourage such efforts to develop new precision medicines as well as to overcome cancer chemoresistance 46 .…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM Structures of the XPF-ERCC1 Endonuclease Reveal an Auto-Inhibited Conformation and the Basis for Activation

Jones

Beuron

Borg

et al. 2019

Preprint

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The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. We report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks ERCC1 DNA-binding elements and restricts access to the XPF catalytic site. Binding of a model DNA junction separates the XPF helical and ERCC1 (HhH) 2 domains, promoting activation. Using these structural data, we propose a model for a 5'-NER incision complex involving XPF-ERCC1-XPA and a DNA junction substrate. Structure-function data suggest xeroderma pigmentosum patient mutations often compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation. 1 in the XPF CM, forming discrete nuclease-NLD and 2x(HhH) 2 functional units. As well as contributing to XPF stability, ERCC1 binds ds/ssDNA substrates and engages the XPA repair protein that is required for NER recruitment 22 . Currently there are no available structures of the XPF HLM or of any full-length XPF-Mus81 family members. By solving the structure of a near full-length human XPF-ERCC1 we have defined its overall architecture and uncovered a previously unreported auto-regulatory mechanism. We show XPF-ERCC1 adopts an auto-inhibited conformer in the absence of DNA in order to prevent promiscuous cleavage and provide structural evidence for initial steps in XPF-ERCC1 activation upon binding a DNA junction. Results Structure determination of human XPF-ERCC1 endonucleaseA single particle cryo-electron microscopy (cryo-EM) density map of purified recombinant XPF-ERCC1 complex (128kDa) (Fig. 1b) was determined at a global resolution of 4.0 Å ( Supplementary Fig. 4b) enabling the assignment of XPF-ERCC1 domain organisation. The map represents the single dominant conformer observed following 3D classification protocols (Supplementary Fig. 3) and exhibits clear secondary structure features throughout ( Fig. 1c and 1d). Local resolution analysis indicated that the heterodimeric 2x(HhH) 2 domain dimer exhibited some mobility, so signal subtraction of this domain was carried out followed by local refinement. This process improved the resolution of the resulting sub-volume to 3.6 Å ( Supplementary Fig. 4d) which enabled de novo building, refinement and validation of an atomic model ( Table 1). The locally-refined map shows clear side-chain density throughout with the local resolution ranging from 3.4 Å in the RecA1 and RecA2 domain cores (Fig. 1c) to 7 Å at the periphery of the ERCC1 NLD. Regions modelled as poly-alanine or omitted from the final structure are shown in Supplementary Table S1. There was ...

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ERCC1-XPF deficiency is a predictor of olaparib induced synthetic lethality and platinum sensitivity in epithelial ovarian cancers

Cited by 33 publications

References 23 publications

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Cryo-EM Structures of the XPF-ERCC1 Endonuclease Reveal an Auto-Inhibited Conformation and the Basis for Activation

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