G‐Quadruplex Loop Length Regulates PARP‐1 Enzymatic Activation

Abstract

Guanine‐rich sequences can interact by Hoogsteen‐hydrogen bonding to form planar quartets that stack into four‐stranded structures known as G‐Quadruplexes (G4DNA). G4DNA is non‐random, overrepresented at key regulatory regions of the cell such as promoters of proto‐oncogenes and telomeres. The overrepresentation in such sites suggests G4DNA serves a significant role in the cell. Poly(ADP‐ribose) polymerase 1 (PARP‐1) is an enzyme that mediates production of polymers of ADP‐ribose units (PAR) that serve as a signal for important cellular processes. PARP‐1 plays a role in the regulation of gene expression, transcription, chromatin remodeling, and DNA repair. Interestingly, PARP‐1 interacts with G4DNA. We show that PARP‐1 binds several G4DNA structures with tight affinity. We also confirm previous evidence revealing that PARP‐1 is enzymatically activated by c‐KIT G4DNA in a DNA structure‐specific manner. In addition, our activity assays reveal that while PARP‐1 binds various G4DNA structures only a subset promote PARP‐1‐mediated PARylation. We show that PARP‐1 enzymatic activation is regulated by G4DNA loop length where longer loops, at least >1 nucleotide, confer higher PARP‐1 activation while shorter loops reduce PARP‐1 activation. Our approach supports a PARP‐1 and G4DNA interaction but emphasizes PARP‐1's catalytic activity is G4DNA loop length‐dependent.Support or Funding InformationNational Institutes of Health Grant R35 GM122601 (to K.D.R.) UAMS Initiative for Maximizing Student Development Program (IMSD) Grant R25 GM083247This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.