7LW7

Human Exonuclease 5 crystal structure

7LW7 の概要

• エントリーDOI: 10.2210/pdb7lw7/pdb
• 分子名称: Exonuclease V, GLYCEROL, IRON/SULFUR CLUSTER, ... (5 entities in total)
• 機能のキーワード: hydrolase
• 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: 39673.09

構造登録者

Tsai, C.L.,Tainer, J.A. (登録日: 2021-02-27, 公開日: 2021-07-14, 最終更新日: 2024-03-06)

主引用文献

Hambarde, S.,Tsai, C.L.,Pandita, R.K.,Bacolla, A.,Maitra, A.,Charaka, V.,Hunt, C.R.,Kumar, R.,Limbo, O.,Le Meur, R.,Chazin, W.J.,Tsutakawa, S.E.,Russell, P.,Schlacher, K.,Pandita, T.K.,Tainer, J.A.
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart.
Mol.Cell, 81:2989-, 2021

PubMed Abstract: Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.

PubMed: 34197737
DOI: 10.1016/j.molcel.2021.05.027

実験手法

X-RAY DIFFRACTION (2.5 Å)