Probing Genome Maintenance Functions of human RECQ1

Abstract

The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in protecting the genome stability in all kingdoms of life. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β. Although the individual RecQ-related diseases are characterized by a variety of clinical features encompassing growth defects (Bloom Syndrome and Rothmund Thomson Syndrome) to premature aging (Werner Syndrome), all these patients have a high risk of cancer predisposition. Here, we present an overview of recent progress towards elucidating functions of RECQ1 helicase, the most abundant but poorly characterized RecQ homolog in humans. Consistent with a conserved role in genome stability maintenance, deficiency of RECQ1 results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased DNA damage and greater sensitivity to certain genotoxic stress. Delineating what aspects of RECQ1 catalytic functions contribute to the observed cellular phenotypes, and how this is regulated is critical to establish its biological functions in DNA metabolism. Recent studies have identified functional specialization of RECQ1 in DNA repair; however, identification of fundamental similarities will be just as critical in developing a unifying theme for RecQ actions, allowing the functions revealed from studying one homolog to be extrapolated and generalized to other RecQ homologs.

Keywords: DNA damage; DNA repair; Helicase; RecQ; genomic instability.

Figure 1

Schematic representation of selected members of the RecQ-Like DNA helicases across species. Members of the RecQ family have many structural motifs that are conserved from bacteria through humans. Besides the core helicase domain, most members possess RecQ C-terminal (RQC) and Helicase and RNase D C-terminal (HRDC) domains that mediate interactions with nucleic acids and proteins. A few RecQ proteins have acidic regions that are responsible for protein-protein interactions. WRN and FFA-1 proteins are unique in that they also contain an exonuclease domain. Total number of amino acids in each protein is indicated on the right and the full color scheme is indicated. Sequence of each protein in FASTA format was used as input to an online server called MyHits (http://myhits.isb-sib.ch/) for the mapping of various motifs in each protein.

Figure 2

Phylogenetic tree for the RecQ-Like proteins of DExH-Box helicase family. Phylogenetic analysis of the selected RecQ DNA helicases was performed using clustalX 2.0 and the image was generated using FigTree version 1.4.0. The branches of the tree are abbreviated with codes and detailed with genus and species name on the right.

Figure 3

Structural insight to the conserved helicase and RQC domains of human RECQ1 helicase (PDB ID: 2v1x). Cartoon representation of a single RECQ1 molecule bound to ADP; color coding of conserved structural domains is consistent with the color scheme in Figure 1. Two RecA-like domains are denoted as RecA1 and RecA2. A. The nucleotide-binding pocket. ADP forms extensive contacts with RecA1 and less with RecA2; residues in contact with ADP are shown as sticks in pink color. B. RecQ-specific Zinc-binding module in RECQ1. A single Zn²⁺ ion is coordinated by four Cys residues positioned on two antiparallel α-helices. C. The winged-helix (WH) domain of RECQ1. β-hairpin is shown in the upper-left corner and the important aromatic residue Tyr 564 is highlighted in red color. The figure was generated using PyMOL (http://www.pymol.org/).