DNA Holliday Junction: History, Regulation and Bioactivity

Abstract

DNA Holliday junction (HJ) is a four-way stranded DNA intermediate that formed in replication fork regression, homology-dependent repair and mitosis, performing a significant role in genomic stability. Failure to remove HJ can induce an acceptable replication fork stalling and DNA damage in normal cells, leading to a serious chromosomal aberration and even cell death in HJ nuclease-deficient tumor cells. Thus, HJ is becoming an attractive target in cancer therapy. However, the development of HJ-targeting ligand faces great challenges because of flexile cavities on the center of HJs. This review introduces the discovery history of HJ, elucidates the formation and dissociation procedures of HJ in corresponding bio-events, emphasizes the importance of prompt HJ-removing in genome stability, and summarizes recent advances in HJ-based ligand discovery. Our review indicate that target HJ is a promising approach in oncotherapy.

Prokaryotic DNA Crossroads: Holliday Junction Formation and Resolution

“…This has been achieved by entrapping, detecting, and quantifying HJs in living cells . Given the widespread occurrence of HJs throughout the genome, recent studies have started to emerge, with a focus on the HJ structure as a pivotal target molecule. ,, While bioactivity research on HJs has been extensively characterized through biochemical and structural studies in eukaryotic paradigms, its extension to prokaryotes remains largely underexplored. For instance, the application of AS1411-modified HJs in the form of aptamers demonstrated a targeted delivery of doxorubicin specifically to murine colon cancer cells in vitro.…”

“…The interaction of these ligands stabilizes DNA junctions that arise through multiple pathways, causing obstruction to replication, transcription, and repair machineries along with the induction of DNA damage response, ultimately leading to cell/bacterial death. 223,228 Consequently, the exploration and advancement of agents targeting HJs could hold significant potential, even for treating microbial infections by selectively influencing the cell divisions of pathogens. 229,230 Unlike the exploration of DNA structures, traditional drug discovery approaches, involving the characterization of enzymes' catalytic sites or protein−DNA or protein−protein complexes associated with HR, have exhibited promising outcomes in preclinical studies.…”

“…In the realm of practical applications, DNA structures that deviate from the conventional double helix, such as quadruplexes, i-motifs, and HJs, have consistently captured attention for their potential therapeutic uses. − These structures also play a crucial role in DNA nanotechnology, contributing to the development of intricate self-assembled nanostructures for applications in functional nanomaterials and drug delivery. − The preceding sections have elucidated that HJ can form both as intermediates in HR and independently of HR when replication forks encounter stalling and regression. The engineered protein derivatives of RuvC have expanded the mapping of genomic footprints of HR at specific DNA breaks in E. coli .…”

“…Collectively, the outcomes of these inhibitor studies strongly indicate that HJs serve as an optimal druggable target, marked by a central cavity capable of accommodating suitable ligands. The interaction of these ligands stabilizes DNA junctions that arise through multiple pathways, causing obstruction to replication, transcription, and repair machineries along with the induction of DNA damage response, ultimately leading to cell/bacterial death. , Consequently, the exploration and advancement of agents targeting HJs could hold significant potential, even for treating microbial infections by selectively influencing the cell divisions of pathogens. , …”

Unveiling the Holliday junction conformational dynamics of upon binding with DNA architectural proteins IHF; A Single molecule FRET approach

“…Holliday Junctions (HJ) play essential roles as intermediates in DNA repair and recombination processes (Liu & West, 2004; Spies & Fishel, 2015) and have recently been identified as structural components of pathogenic biofilms (Devaraj et al , 2019). These dynamic structural motifs exhibit a propensity of structural flexibility, existing in diverse conformations (Lilley, 2000; Song et al , 2022). The structural details of HJs, as revealed by X-ray crystallography studies, manifests as an intersection of four DNA strands and exchanging in a central region (Eichman et al , 2000).…”