Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

• DOI: 10.1016/j.molcel.2014.03.014
• Publication Date: 2014-04-10T17:15:51Z
• Authors: Michael R.G. Hods...; Jan Silhan; Gerry P. Crossan; Juan I. Garaycoechea; Shivam Mukherjee; Christopher M. Jo...; Orlando D. Schärer; Ketan J. Patel
• Keywords: ERCC1; Nuclease

SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), its deficiency leads genomic instability, sensitivity DNA crosslinking agents, Fanconi anemia. However, it is not understood how associated act in crosslink repair. Here, we uncover consequences of mouse Slx4 reveal function Slx4-deficient mice develop epithelial cancers have a contracted hematopoietic stem cell pool. The N-terminal domain (mini-SLX4) that only XPF-ERCC1 sufficient confer resistance agents. Recombinant mini-SLX4 enhances nuclease activity up 100-fold, directing specificity toward forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around embedded synthetic replication fork, an essential step the repair this lesion. These observations define vertebrate as tumor suppressor, which activates