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WEE1 kinase protects the stability of stalled DNA replication forks by limiting CDK2 activity

Camilla Reiter Elbæk1, Valdemaras Petrosius2, Jan Benada2

  • 1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløesvej 5, Copenhagen N 2200, Denmark; Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Kongens Lyngby 2800, Denmark.

Cell Reports
|January 19, 2022
PubMed

Insights

WEE1 kinase activity protects nascent DNA from degradation at stalled replication forks. WEE1 inhibition leads to DNA2-mediated fork degradation, highlighting its role in genome stability and cancer therapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cellular feedback systems are crucial for genome maintenance during DNA replication.
  • When replication forks stall, protective pathways prevent excessive DNA nuclease activity.
  • The role of WEE1 in protecting stalled replication forks is not fully understood.

Purpose of the Study:

  • To investigate the role of WEE1 in protecting nascent DNA at stalled replication forks.
  • To identify the nuclease responsible for DNA degradation when WEE1 is inhibited.
  • To explore the therapeutic implications of WEE1's role in genome stability.

Main Methods:

  • Cell-based assays to monitor DNA replication fork stability.
  • WEE1 inhibition and CDK2 activity measurements.
  • Identification of nucleases involved in DNA degradation using genetic approaches.

Main Results:

  • WEE1 activity is essential for guarding nascent DNA against degradation at stalled forks.
  • WEE1-dependent suppression of cyclin-dependent kinase 2 (CDK2) activity counteracts fork degradation.
  • DNA2 was identified as the nuclease responsible for excessive fork degradation in WEE1-inhibited cells.
  • WEE1's role in fork protection is distinct from CHK1 and p21.

Conclusions:

  • WEE1 plays a critical, previously unrecognized role in protecting stalled replication forks.
  • WEE1 inhibition induces significant genome instability, primarily through DNA2-mediated degradation.
  • Targeting WEE1 may offer a therapeutic strategy against cancers with high replication stress.
Keywords:
CDKDNA replicationWEE1cancercell cyclefork protectiongenome integritynucleasesreplication stress

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