Kinase-independent role for CRAF-driving tumour radioresistance via CHK2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26333361.
- Also identified by DOI 10.1038/ncomms9154 and PMC identifier 4559870.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.
Medical subject headings
- Checkpoint Kinase 2
- DNA Damage
- Proto-Oncogene Proteins c-raf
- Radiation Tolerance
- Radiation, Ionizing
- p21-Activated Kinases