2. Academic Validation
  3. Removal of RTF2 from Stalled Replisomes Promotes Maintenance of Genome Integrity

Removal of RTF2 from Stalled Replisomes Promotes Maintenance of Genome Integrity

  • Mol Cell. 2018 Jan 4;69(1):24-35.e5. doi: 10.1016/j.molcel.2017.11.035.
Molly C Kottemann 1,  Brooke A Conti 1,  Francis P Lach 1,  Agata Smogorzewska 2
Affiliations

Affiliations

  • 1 Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
  • 2 Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA. Electronic address: asmogorzewska@rockefeller.edu.
PMID: 29290612 DOI: 10.1016/j.molcel.2017.11.035
Abstract

The protection and efficient restart of stalled replication forks is critical for the maintenance of genome integrity. Here, we identify a regulatory pathway that promotes stalled forks recovery from replication stress. We show that the mammalian replisome component C20orf43/RTF2 (homologous to S. pombe Rtf2) must be removed for fork restart to be optimal. We further show that the proteasomal shuttle proteins DDI1 and DDI2 are required for RTF2 removal from stalled forks. Persistence of RTF2 at stalled forks results in fork restart defects, hyperactivation of the DNA damage signal, accumulation of single-stranded DNA (ssDNA), sensitivity to replication drugs, and chromosome instability. These results establish that RTF2 removal is a key determinant for the ability of cells to manage replication stress and maintain genome integrity.

Keywords

C20orf43; DDI1; DDI2; DNA replication; RTF2; aphidicolin; hydroxyurea; iPOND; replication stress; ubiquitin proteasome system.

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