7LIP

X-ray structure of SPOP MATH domain (D140G)

7LIP の概要

• エントリーDOI: 10.2210/pdb7lip/pdb
• 分子名称: Speckle-type POZ protein, SULFATE ION (3 entities in total)
• 機能のキーワード: spop, 53bp1, dna damage response, homologous recombination, ubiquitin ligase, protein binding
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16627.08

構造登録者

Botuyan, M.V.,Cui, G.,Mer, G. (登録日: 2021-01-27, 公開日: 2021-04-14, 最終更新日: 2023-10-18)

主引用文献

Wang, D.,Ma, J.,Botuyan, M.V.,Cui, G.,Yan, Y.,Ding, D.,Zhou, Y.,Krueger, E.W.,Pei, J.,Wu, X.,Wang, L.,Pei, H.,McNiven, M.A.,Ye, D.,Mer, G.,Huang, H.
ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.
Sci Adv, 7:-, 2021

PubMed Abstract: 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.

PubMed: 34144977
DOI: 10.1126/sciadv.abd9208

実験手法

X-RAY DIFFRACTION (1.48 Å)