Ryan, B. | Search bioRxiv

bioRxiv2021

Cytoplasmic Switch of ARS2 Isoforms Promotes Nonsense-Mediated mRNA Decay and Arsenic Sensitivity

The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), bound to the cap binding complex (CBC). We report here that alternative splicing of ARS2s intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to NCBP1, ERF1 and DHX34, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress, where cytoplasmic ARS2 promotes a global response to arsenic in a CBC-independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, stress response, and cancer treatment.

molecular biology↗

bioRxiv2021

Using a recently approved tumor mutational burden biomarker to stratify patients for immunotherapy may introduce a sex bias

The U.S. Food and Drug Administration (FDA) recently approved the treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for patients with advanced solid tumors with a high tumor mutational burden (TMB) (defined as TMB [≥]10 mutations/Mb). However, following recent studies suggest that TMB levels and response to ICI treatment may differ between male and female melanoma patients, we investigated whether using this high-TMB threshold for selecting patients for anti-PD1 treatment may induce a sex-dependent bias. We analyzed a large ICI cohort of 1,286 patients across nine cancer types treated with anti-PD1/PDL1. We find that using this threshold would indeed result in an unwarranted sex bias in melanoma, successfully stratifying female but not male patients. While this threshold is currently not a regulatory prerequisite for ICI treatment in melanoma, it is important to raise awareness to this bias. Notably, no sex-dependent significant differences were observed in the response of melanoma patients to anti-CTLA4 therapies, different chemotherapies or combination therapies. Beyond melanoma, the high-TMB threshold additionally introduces a sex bias of considerable magnitude in glioblastoma and in patients with cancers of unknown origin, however, these results are not statistically significant. A power analysis shows that these biases may become significant with larger sample size, warranting further careful testing in larger cohorts.

cancer biology↗