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Article
| Open Access
Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open Access
PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
TOP1 resolves DNA supercoils by forming cleavage complexes (TOP1cc) that are trapped by TOP1 inhibitors. Here the authors provide insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG results in stabilization of TOP1cc PARylation that blocks the proteasomal degradation of TOP1cc.
- Yilun Sun
- , Jiji Chen
- & Yves Pommier
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Article
| Open Access
DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine
7,8-dihydro-8-oxoguanine and 7,8-dihydro-8-oxoadenine (oxoA) are generated upon oxidative damage to DNA, but the biological effects of oxoA are not well known. Here, the authors report that only oxoA forms DNA interstrand crosslinks (ICLs) upon secondary oxidation and that these ICLs can be induced by reactive halogen species, one-electron oxidants and the myeloperoxidase/H2O2/Cl- system.
- Aaron L. Rozelle
- , Young Cheun
- & Seongmin Lee
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Article
| Open Access
Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma
Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.
- Stefan Antonowicz
- , Zsolt Bodai
- & George B. Hanna
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Article
| Open Access
Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search
It is not fully understood how XPA interacts with a DNA lesion during nucleotide excision repair. Here, the authors use single molecule analysis to study XPA–DNA interactions, including the DNA bend angle, protein stoichiometry, and diffusive properties during damage search.
- Emily C. Beckwitt
- , Sunbok Jang
- & Bennett Van Houten
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Article
| Open Access
Occurrence and repair of alkylating stress in the intracellular pathogen Brucella abortus
It is assumed that intracellular pathogenic bacteria must cope with DNA alkylating stress within host cells. Here, Poncin et al. show that the pathogen Brucella abortus does encounter alkylating stress within macrophages, and shed light into the pathways required for DNA repair in this organism.
- Katy Poncin
- , Agnès Roba
- & Xavier De Bolle
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Article
| Open Access
A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome
Topoisomerase 2 (Top2) is known to resolve DNA topological stress through double strand breaks (DSBs), yet Top2 inhibition has been reported to result in a significant amount of single-strand breaks (SSBs). Here the authors develop CC-seq—a method that allows direct mapping of both Top2-linked SSBs and DSBs—and reveal a significant impact of primary DNA sequence on Top2 directed cleavage.
- William H. Gittens
- , Dominic J. Johnson
- & Matthew J. Neale
Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes