Abstract
Although homologous recombination (HR) is indicated as a high-fidelity repair mechanism, break-induced replication (BIR), a subtype of HR, is a mutagenic mechanism that leads to chromosome rearrangements. It remains poorly understood how cells suppress mutagenic BIR. Trapping of Topoisomerase 1 by camptothecin (CPT) in a cleavage complex on the DNA can be transformed into single-ended double-strand breaks (seDSBs) upon DNA replication or colliding with transcriptional machinery. Here, we demonstrate a role of Abraxas in limiting seDSBs undergoing BIR-dependent mitotic DNA synthesis. Through counteracting K63-linked ubiquitin modification, Abraxas restricts SLX4/Mus81 recruitment to CPT damage sites for cleavage and subsequent resection processed by MRE11 endonuclease, CtIP, and DNA2/BLM. Uncontrolled SLX4/MUS81 loading and excessive end resection due to Abraxas-deficiency leads to increased mitotic DNA synthesis via RAD52- and POLD3- dependent, RAD51-independent BIR and extensive chromosome aberrations. Our work implicates Abraxas/BRCA1-A complex as a critical regulator that restrains BIR for protection of genome stability.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Camptothecin / pharmacology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Chromatin / genetics
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Chromatin / metabolism*
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DNA Breaks, Double-Stranded
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DNA Damage / drug effects*
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DNA Damage / genetics
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DNA Polymerase III / metabolism
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DNA Replication / genetics
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DNA Topoisomerases, Type I / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endonucleases / genetics
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Endonucleases / metabolism*
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Homologous Recombination
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Humans
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MRE11 Homologue Protein / metabolism
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Mice
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RNA, Small Interfering
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Rad52 DNA Repair and Recombination Protein / genetics
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Rad52 DNA Repair and Recombination Protein / metabolism
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Recombinases / genetics
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Recombinases / metabolism*
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Topoisomerase I Inhibitors / pharmacology
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Ubiquitination
Substances
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ABRAXAS1 protein, human
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Carrier Proteins
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Chromatin
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DNA-Binding Proteins
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MRE11 protein, human
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RAD52 protein, human
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RNA, Small Interfering
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Rad52 DNA Repair and Recombination Protein
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Recombinases
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Topoisomerase I Inhibitors
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POLD3 protein, human
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DNA Polymerase III
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Endonucleases
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MRE11 Homologue Protein
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MUS81 protein, human
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SLX4 protein, human
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DNA Topoisomerases, Type I
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TOP1 protein, human
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Camptothecin