2. Academic Validation
  3. EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2

EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2

  • Mol Cell. 2019 Aug 8;75(3):605-619.e6. doi: 10.1016/j.molcel.2019.05.026.
Jadwiga Nieminuszczy 1,  Ronan Broderick 1,  Marina A Bellani 2,  Elizabeth Smethurst 3,  Rebekka A Schwab 3,  Veronica Cherdyntseva 4,  Theodora Evmorfopoulou 4,  Yea-Lih Lin 5,  Michal Minczuk 6,  Philippe Pasero 5,  Sarantis Gagos 4,  Michael M Seidman 2,  Wojciech Niedzwiedz 7
Affiliations

Affiliations

  • 1 The Institute of Cancer Research, London, UK.
  • 2 Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD, USA.
  • 3 Institute of Molecular Medicine, Oxford, UK.
  • 4 Laboratory of Genetics, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 5 Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France.
  • 6 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • 7 The Institute of Cancer Research, London, UK. Electronic address: [email protected].
PMID: 31255466 DOI: 10.1016/j.molcel.2019.05.026
Abstract

Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including Cancer. Key to this process is the cells' ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1's inhibition in EXD2-/- cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2's nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2's depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection.

Keywords

BRCA1; BRCA2; DNA replication; EXD2; EXDL2; fork regression.

Figures