Molecular Mechanisms of RecQ Helicases in Genome Maintenance

Schematic representation of some of the best characterized members of the RecQ family color coded according to their structural domains. Proteins are aligned according to the conserved helicase domain, which is shown in yellow. The conserved RecQ-C-terminal (RQC) and helicase-and-RNaseD-like-C-terminal (HRDC) domains are shown in red and green, respectively. The exonuclease domain in the amino-terminal region of WRN is shown in pink. Regions containing patches of acidic residues are shown in blue. The nuclear localization signal sequences identified at the extreme carboxyl terminus of certain family members is shown as a brown bar. The remaining portions of each protein (gray) represent regions that are poorly conserved. The sizes of the individual domains are not to scale. At least three splice variants of the human RECQ5 protein are expressed, of which only the largest (β-isoform) is shown. The crystal structure of human RECQ1 in complex with ADP is also shown (PDB ID: 2v1x).

RecQ DNA helicases are critical enzymes for the maintenance of genome integrity. Studies of RecQ helicases in model prokaryotic and eukaryotic systems have demonstrated their vital roles in DNA replication, recombination, and repair. RecQ proteins function as ATP-dependent motors that operate on an unparalleled breath of DNA substrates ranging from linear DNA duplexes to fork DNA and Holliday junction structures. However, the physical mechanisms by which RecQ helicases recognize and process this unparalleled breath of DNA substrates are largely unknown. Another key question is why humans have five different RecQ helicases, while other organisms such as bacteria and yeast have only one or two. Strikingly, mutations affecting three of the five human RecQ helicases cause distinct genetic diseases, all of which display high predisposition to cancer. The unique clinical features of these disorders support the notion that the different RecQ helicases have non-overlapping functions, but the molecular basis for their different enzymatic activities remains unclear. Our goal is to define the distinct molecular mechanisms of the five human RecQ helicases in genome maintenance.

Our current focus is to combine biochemical and structural approaches to determine the molecular mechanisms by which RecQ helicases link their ATPase, DNA binding, and DNA unwinding/branch migration functions to process central intermediates of DNA replication and repair.