Abstract 94: PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers

Abstract

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5. Current efforts are focused on understanding whether PRMT5-substrate adaptor disruption synergizes with immune therapies or new classes of PRMT5 inhibitors in CDKN2A/MTAP null cancer. Citation Format: Kathleen M. Mulvaney, Brian McMillan, Christa Blomquist, Nischal Acharya, Matthew Ranaghan, Devishi Kesar, Alessandra Ianari, William Sellers. PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 94.

Prognostic value of CDKN2A in head and neck squamous cell carcinoma via pathomics and machine learning

“…Building upon the foundational work in the field, our findings echo and extend the narrative around CDKN2A's prognostic significance in cancer 24–26 . For instance, Swati et al.…”

“…Building upon the foundational work in the field, our findings echo and extend the narrative around CDKN2A's prognostic significance in cancer. [24][25][26] For instance, Swati et al's 27 investigation into the relationship between CDKN2A/p16 expression and recurrence in Indian oral squamous cell carcinoma aligns with our insights, underlining the gene's broader applicability as a biomarker. Likewise, research by Madelene et al, 28 utilizing 5-aza-2'deoxycytidine (5-aza-dC) to reactivate p16 in Tu159 HNSCC cells, resulting in inhibited tumour growth, supports the functional implications of CDKN2A expression we observed.…”