7lio
X-ray structure of SPOP MATH domain (S119D) in complex with a 53BP1 peptide
Structural highlights
FunctionSPOP_HUMAN Inhibits IPF1/PDX1 transactivation of established target promoters, such as insulin, may be by recruiting a repressor complex (By similarity). In complex with CUL3, involved in ubiquitination of BMI1, H2AFY and DAXX, and probably also in ubiquitination and proteasomal degradation of Gli2 or Gli3.[1] [2] [3] Publication Abstract from PubMed53BP1 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. ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.,Wang D, Ma J, Botuyan MV, Cui G, Yan Y, Ding D, Zhou Y, Krueger EW, Pei J, Wu X, Wang L, Pei H, McNiven MA, Ye D, Mer G, Huang H Sci Adv. 2021 Jun 18;7(25). pii: 7/25/eabd9208. doi: 10.1126/sciadv.abd9208., Print 2021 Jun. PMID:34144977[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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