RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

At present, the mechanism for chemotherapy-dependent RNA disruption is unknown. A mechanism for rRNA degradation induced by nutritional deficit, called ribophagy, has been described and shown to be distinct from general autophagy [9] . Specific ubiquitination and deubiquitination can protect against or promote ribophagy, indicating an important role for the ubiquitin status of the ribosome in determining susceptibility to ribophagy [9, 42] . However, chemotherapy drug-induced rRNA disruption occurs without any known nutritional deficit and is irreversible after sufficient rRNA disruption has occurred, while ribophagy appears to promote survival during extended nutritional deprivation. A second mechanism for the selective removal of non-functional ribosomes, non-functional rRNA Decay (NRD), has also been described [3, 4, 8, 43] . While ubiquitin also plays a role in NRD, different proteins from those involved in ribophagy appear to be involved, including factors known to act in DNA repair. While we cannot rule out either ribophagy or NRD at this time as mechanisms of ribosomal decay contributing to rRNA disruption, it is worth noting that the generation of specific high molecular weight rRNA fragments has not yet been reported as associated with either ribophagy or NRD.