The Schlafen family of proteins have relatively unknown molecular mechanisms and biological functions. Here we study the novel functions of one member in the human Slfn family, huSlfn11, and its role in regulating the DNA damage response (DDR) as well as its ability to stabilize Z-DNA. We found that huSlfn11-expressing cancer cells treated with camptothecin (CPT) display selective inhibition of ATR (ataxia-telangiectasia mutated and RAD3- related) protein translation efficiency. This selective regulation by huSlfn11 is based on the codon usage of ATR. We have also demonstrated that cancer cells deficient in huSlfn11 expression can be completely re-sensitized to CPT by knocking down the expression of ATR, and moderately re- sensitizied to CPT with the use of ATR inhibitors. Additionally, we have shown for the first time, that huSlfn11N, the C-terminal truncation of full length huSlfn11 that includes the ATPase AAA domain, can stabilize Z-DNA conformation, possibly as a novel antiviral mechanism

Transcriptome analysis reveals a strong positive correlation between human Schlafen family member 11 (SLFN11) expression and the sensitivity of tumor cells to DNA-damaging agents (DDAs). Here, we show that SLFN11 preferentially inhibits translation of the serine/threonine kinases ATR and ATM upon DDA treatment based on distinct codon usage without disrupting early DNA damage response signaling. Type II transfer RNAs (tRNAs), which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. Messenger RNAs encoded by genes with high TTA (Leu) codon usage, such as ATR, display utmost susceptibility to translational suppression by SLFN11. Specific attenuation of tRNA-Leu-TAA sufficed to ablate ATR protein expression and restore the DDA sensitivity of SLFN11-deficient cells. Our study uncovered a novel mechanism of codon-specific translational inhibition via SLFN11-dependent tRNA cleavage in the DNA damage response and supports the notion that SLFN11-deficient tumor cells can be resensitized to DDAs by targeting ATR or tRNA-Leu-TAA.

Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor a (TNFalpha). Anti-TNFalpha regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFalpha therapy as a novel and immediately accessible (co)treatment for DLBCL.