ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication

Sci Adv. 2021 Jun 18;7(25):eabd9208. doi: 10.1126/sciadv.abd9208. Print 2021 Jun.


53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase-catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin* / genetics
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair
  • DNA Replication
  • Nuclear Proteins
  • Recombinational DNA Repair
  • Repressor Proteins
  • Tumor Suppressor p53-Binding Protein 1


  • Chromatin
  • Nuclear Proteins
  • Repressor Proteins
  • Tumor Suppressor p53-Binding Protein 1