SLFN11 in replication stress tolerance in cancer and therapy resistance

SLFN11 is silenced in ~50% of all cancers and is the strongest predictor of chemotherapy resistance. Since replication stress-inducing agents activate SLFN11 as a tRNA nuclease triggering translation shutdown and p53-independent apoptosis, we hypothesize that loss of this safeguarding mechanism confers replication stress tolerance and the emergence of therapy-resistance. Insights into the repertoire of SLFN11’s cellular functions, how it is activated by replication stress but constrained during normal DNA replication, why it is silenced in treatment naïve cancers and its role during tumour evolution and are currently unknown. We recently: 1) established that SLFN11 senses and is activated by unprotected ssDNA following RPA exhaustion, 2) discovered NSUN2 and FAM122A as co-factors that cooperate with SLFN11 to eliminate cells with heightened replication stress, 3) uncovered a non-canonical function of SLFN11 and NSUN2 independent of the SLFN11 tRNA nuclease activity and translation shutdown, and 4) implicated SLFN11 loss as a key determinant in the survival of ATRX deficient cells during telomere crisis and ALT establishment. Based on these discoveries, we propose a multi-disciplinary strategy using genetics, proteomics, biochemistry and biophysical approaches to interrogate the function(s) and regulation of SLFN11 in replication stress tolerance, with implications for cancer development and therapy resistance.