7lin

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X-ray structure of SPOP MATH domain (D140G) in complex with a 53BP1 peptideX-ray structure of SPOP MATH domain (D140G) in complex with a 53BP1 peptide

Structural highlights

7lin is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.44Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SPOP_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 PubMed

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.

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 Also

References

  1. ↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
  2. ↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
  3. ↑ Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200
  4. ↑ 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. ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication. Sci Adv. 2021 Jun 18;7(25). pii: 7/25/eabd9208. doi: 10.1126/sciadv.abd9208., Print 2021 Jun. PMID:34144977 doi:http://dx.doi.org/10.1126/sciadv.abd9208

7lin, resolution 1.44Å

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