Chromosome 17q gain is by far the most common DNA copy number alteration in aggressive neuroblastoma (NB) but the causal 17q drivers remain to be identified due to the large size of the recurrently involved chromosome segments. Integrated mRNA/CNV analysis of 211 NBs with the CONEXIC algorithm identified the DNA helicase BRIP1 (alias FANCJ) as top-ranked candidate 17q driver gene. Stable BRIP1 knock down in NB cell lines significantly reduced cell viability and colony forming capacity. In keeping with its role in DNA damage repair, knock down induced DNA damage as evidenced by increased γH2AX. Given that BRIP1 also unwinds G-quadruplex (G4) DNA structures, we hypothesized that increased BRIP1 levels could protect NB cells from MYCN induced replicative stress and install what we call "replicative stress resistance". Knock down increases RPA32 protein levels and decreases sensitivity to hydroxy urea induced replication fork stalling as measured by DNA combing. Next, we assumed that the dependency to G4 unwinding of cancer cells would render them sensitive to G4 stabilising ligands and indeed observed strong effects on viability upon treatment with TMPYP4. Gene expression profiling after BRIP1 knock down confirmed enrichment for gene sets implicated in DNA replication and repair. Next, overexpression of BRIP1 in dβh-MYCN-eGFP transgenic zebrafish caused accelerated tumor formation. We are now using this model to screen for synergism between G4 stablising ligands such as TMPYP4 and pyridostatin by oral gavage in zebrafish to assess possible synergistic effects as a prelude to novel therapies for high risk NB. In conclusion, we propose BRIP1 as a major 17q cooperative driver oncogene in NB by providing replicative stress resistance to highly replicative NB cells at G4s, offering a new entry point for drugging of aggressive high risk NB.