Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268140 (XPF)
 549 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RecQ DNA helicases, human BLM and yeast Sgs1, form a complex with topoisomerase III (Top3) and are thought to act during DNA replication to restart forks that have paused due to DNA damage or topological stress. We have shown previously that yeast cells lacking SGS1 or TOP3 require MMS4 and MUS81 for viability. Here we show that Mms4 and Mus81 form a heterodimeric structure-specific endonuclease that cleaves branched DNA. Both subunits are required for optimal expression, substrate binding, and nuclease activity. Mms4 and Mus81 are conserved proteins related to the Rad1-Rad10 (XPF/ERCC1) endonuclease required for nucleotide excision repair (NER). However, the Mms4-Mus81 endonuclease is 25 times more active on branched duplex DNA and replication fork substrates than simple Y-forms, the preferred substrate for the NER complexes. We also present genetic data that indicate a novel role for Mms4-Mus81 in meiotic recombination. Our results suggest that stalled replication forks are substrates for Mms4-Mus81 cleavage-particularly in the absence of Sgs1 or BLM. Repair of this double-strand break (DSB) by homologous recombination may be responsible for the elevated levels of sister chromatid exchange (SCE) found in BLM(-/-) cells.
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PMID:Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease. 1164 Dec 78

Topoisomerases are essential enzymes solving DNA topological problems such as supercoils, knots and catenanes that arise from replication, transcription, chromatin remodeling and other nucleic acid metabolic processes. They are also the targets of widely used anticancer drugs (e.g. topotecan, irinotecan, enhertu, etoposide, doxorubicin, mitoxantrone) and fluoroquinolone antibiotics (e.g. ciprofloxacin and levofloxacin). Topoisomerases manipulate DNA topology by cleaving one DNA strand (TOP1 and TOP3 enzymes) or both in concert (TOP2 enzymes) through the formation of transient enzyme-DNA cleavage complexes (TOPcc) with phosphotyrosyl linkages between DNA ends and the catalytic tyrosyl residue of the enzymes. Failure in the self-resealing of TOPcc results in persistent TOPcc (which we refer it to as topoisomerase DNA-protein crosslinks (TOP-DPC)) that threaten genome integrity and lead to cancers and neurodegenerative diseases. The cell prevents the accumulation of topoisomerase-mediated DNA damage by excising TOP-DPC and ligating the associated breaks using multiple pathways conserved in eukaryotes. Tyrosyl-DNA phosphodiesterases (TDP1 and TDP2) cleave the tyrosyl-DNA bonds whereas structure-specific endonucleases such as Mre11 and XPF (Rad1) incise the DNA phosphodiester backbone to remove the TOP-DPC along with the adjacent DNA segment. The proteasome and metalloproteases of the WSS1/Spartan family typify proteolytic repair pathways that debulk TOP-DPC to make the peptide-DNA bonds accessible to the TDPs and endonucleases. The purpose of this review is to summarize our current understanding of how the cell excises TOP-DPC and why, when and where the cell recruits one specific mechanism for repairing topoisomerase-mediated DNA damage, acquiring resistance to therapeutic topoisomerase inhibitors and avoiding genomic instability, cancers and neurodegenerative diseases.
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PMID:Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC). 3220 Feb 33