2020
DOI: 10.1038/s41467-020-15000-w
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TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

Abstract: Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate-a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)-is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-canc… Show more

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Cited by 79 publications
(89 citation statements)
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“…In agreement, it has been proposed that recruitment of SPRTN to chromatin upon formaldehyde exposure requires a ubiquitylation signal ( Borgermann et al., 2019 ). Moreover, SPRTN recruitment to TOP1 DPCs depends on direct interaction between the protease and the adaptor protein TEX264 ( Fielden et al., 2020 ). Hence, initial recruitment appears to be highly context-dependent.…”
Section: Discussionmentioning
confidence: 99%
“…In agreement, it has been proposed that recruitment of SPRTN to chromatin upon formaldehyde exposure requires a ubiquitylation signal ( Borgermann et al., 2019 ). Moreover, SPRTN recruitment to TOP1 DPCs depends on direct interaction between the protease and the adaptor protein TEX264 ( Fielden et al., 2020 ). Hence, initial recruitment appears to be highly context-dependent.…”
Section: Discussionmentioning
confidence: 99%
“…Notably, recruitment of SPRTN to UV-induced lesions (but not DPCs) has been shown to depend on the UBZ domain potentially indicating that this domain serves dual purposes ( 20–22 ). However, how SPRTN is recruited to DPCs remains controversial with evidence pointing towards ubiquitylation or SUMOylation signals ( 39 , 40 ). Understanding how the presence of crosslinks is signalled to DPC repair enzymes will be critical to decipher decision making during DPC repair.…”
Section: Discussionmentioning
confidence: 99%
“…Several other proteases were proposed to function in DPC proteolysis -GCNA, a mammalian SPRTN homologue (Bhargava et al, 2020;Borgermann et al, 2019;Dokshin et al, 2020), the serine protease FAM111A (Kojima et al, 2020), as well as the yeast aspartic protease Ddi1 (Serbyn et al, 2020). The Cdc48 molecular segregase (p97 in mammals) also assists the Top1cc extraction process (Fielden et al, 2020;Nie et al, 2012;Stingele et al, 2014). Following partial proteolysis, Top1 peptides that remain attached to the single stranded (ss) DNA break can be further removed by the canonical DNA repair pathways such as nucleotide or base excision repair (NER and BER) involving the aforementioned nucleases and TDP1, as well as PARP1, PNKP, polymerase b, and DNA ligase (Mei et al, 2020;Pommier et al, 2006).…”
Section: Introductionmentioning
confidence: 99%