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Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage

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  • Xiao Wu

    (The University of Texas MD Anderson Cancer Center)

  • Bin Wang

    (The University of Texas MD Anderson Cancer Center
    The MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences)

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.

Suggested Citation

  • Xiao Wu & Bin Wang, 2021. "Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24665-w
    DOI: 10.1038/s41467-021-24665-w
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    Cited by:

    1. Huimin Zhang & Yun Xiong & Dan Su & Chao Wang & Mrinal Srivastava & Mengfan Tang & Xu Feng & Min Huang & Zhen Chen & Junjie Chen, 2022. "TDP1-independent pathways in the process and repair of TOP1-induced DNA damage," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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