Genomes and G-quadruplexes: for better or for worse

Genomic integrity is crucial for correct chromosome segregation and physiological rates of cell proliferation. Mutations, deletions and translocations, hallmarks of human tumors, drive the aberrant proliferation and metastatic behavior of cancer cells. These chromosomal rearrangements often occur at genomic sites susceptible to breakage during DNA replication, including regions with G-quadruplex (G4)-forming potential. G4s are stable secondary structures that guanine-rich single-stranded DNA can readily adopt in vitro. However, their formation in eukaryotic cells has remained elusive and thus a subject of debate ever since they were first described. Recent work has more convincingly implicated G4s in a variety of biological processes including telomere maintenance, gene expression, epigenetic regulation and DNA replication. However, the downside of employing thermodynamically very stable alternative DNA structures as regulatory entities lies in their potential to also interfere with normal DNA metabolic processes, such as transcription and replication, which require readability of each base to faithfully transmit genetic information. Indeed, it has become clear that G4 structures can pose prominent barriers to replication fork progression and that they are also intrinsically recombinogenic. Here, we discuss mechanisms that cells evolved to counteract these detrimental effects, thereby ensuring the faithful inheritance of G4-containing genomes.