PARP1异构体及其与核仁素相互作用的全面计算研究：结构洞见及对乳腺癌的意义

Poly(ADP-ribose) polymerase 1 (PARP1) has emerged as a key player and a promising focal point in dysregulated DNA repair in breast cancer. PARP1 exists in multiple isoforms, each with a unique combination of domains [zinc finger - Poly(ADP-ribose) polymerase (zf-PARP), Poly(ADP-ribose) polymerase1domain (PADR1), Tryptophan-Glycine-Arginine domain (WGR), and BRCA1 C Terminus (BRCT)]. High expression of PARP1 is frequently associated with an aggressive type of breast cancer and poor prognosis. We earlier predicted PARP1 as a common interactor of the RNA-binding protein, nucleolin (NCL) and BRCA1 where its BRCT domain is implicated in protein interactions. In a published study we showed NCL-miR interfaces for the six frequently dysregulated miRNA in breast cancer including miR-221. While NCL regulates miR-221 expression, PARP1 is a target of miR-221. These and other studies strongly suggest NCL-PARP1 collaborate at the damaged DNA sites. In this study, we built structural models of the PARP1 isoforms and performed docking analyses using ClusPro and HDOCK using a full-length structural model of NCL to assess their interactions. Our results revealed isoform-specific NCL-PARP1 interaction interfaces. The data is strongly suggestive that differences in domain architecture across PARP1 isoforms can alter protein-protein interactions with potential distinct functional implications. Isoform-specific PARP1-NCL-interactions thus can govern DNA repair processes. Next, we examined how cancer-associated mutations in PARP1 affect these interactions. Using ENSEMBL, COSMIC, and TCGA, we selected key mutations with breast cancer phenotypes and created in silico models of PARP1. The generated comparative analyses of mutant and wild-type isoforms revealed mutation-driven alterations in the interaction interfaces . Overall, our study sheds light on the structural and functional diversity of PARP1 isoforms, how they interact with NCL, and how specific mutations could influence breast cancer tumorigenesis. PARP inhibitors are frequently used as targeted cancer therapeutics. Understanding the molecular insights about how PARP-isoforms interact with its protein partners involved in DNA repair process will be valuable and can serve as the initial steps towards the development of potential therapeutic interventions.