RBBP9 interactors in Fanconi Anaemia

The Fanconi Anaemia (FA) pathway resolves replication fork-stalling inter-strand crosslinks (ICLs) and is mutated in Fanconi anaemia. FA is a rare recessive chromosomal instability syndrome, resulting in hypersensitivity to DNA-crosslinkers, and particularly disadvantageous for stem cell growth and maintenance. FA individuals have an increased risk to haematological malignancies (AML) and head-and-neck squamous cell carcinomas (HNSCC), often very aggressive. Systemic intolerance due to somatic cell hypersensitivity to standard chemo-radio-therapy in patients limits treatment options in FA-HNSCC underscoring an urgent, unmet need to develop novel therapeutic strategies. Here, we performed unbiased functional genomic siRNA screens to unveil genetic interactions that are synthetic lethal with FA pathway deficiency, in a panel of patient-derived, FA-core-complex mutated HNSCC cell lines. We identified RBBP9, LAMTOR2, PSMB2 and PSMC1, among others, as potential FA-HNSCC-specific hits. We demonstrate that RBBP9, a poorly characterized serine hydrolase is synthetically lethal in FA-defective HNSCC and crucial for FA-HNSCC survival. RBBP9 interaction partners are identified in a RBBP9-FLAG IP-MS experiment.