Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology

Abstract

Helicases use the energy of ATP hydrolysis to separate double-stranded nucleic acids to facilitate essential processes such as replication, recombination, transcription and repair. This article focuses on the human RECQ helicase gene and protein family. Loss of function of three different members has been shown to cause Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS). This article outlines clinical and cellular features of these cancer predisposition syndromes, and discusses their pathogenesis in light of our understanding of RECQ helicase biochemical activities and in vivo functions. I also discuss the emerging role for RECQ helicases as predictors of disease risk and the response to therapy.

Fig. 1

Human RECQ helicase gene and protein family. The five human RECQ helicase proteins are shown as boxes (center). Gene symbols and gene chromosomal locations are given to the left, and encoded catalytic activities to the right, of each protein diagram. All five proteins share a central, conserved RECQ helicase domain that encodes a 3′–5′ helicase activity. Three family members contain RECQ Consensus (RQC) domains, and two a Helicase and RNase D C-terminal (HRDC) domain. Nuclear localization signals (NLS) are depicted as short filled boxes. The 3′–5′ exonuclease domain is unique to WRN, whereas the Sld2 homology domain is found only in RECQL4.

Fig. 2

Disease-causing mutations in human RECQ helicase genes. WRN, BLM and RECQL4 open reading frames are depicted as boxes with domains indicated as in Fig. 1. Two additional acidic domains are shown for WRN: the acidic repeat domain (acidic) and a short hyperacidic (ha) stretch consisting of aspartic and glutamic acid residues preceding the helicase domain. Residue and bp coordinates are shown to the left of the beginning of each protein. Coding region non-synonymous SNP polymorphisms are shown above, and clinically ascertained mutations below, each RECQ protein. Mutations, not consequences, are shown; and only single examples of specific mutations. The WRN R834C SNP polymorphism is circled (see text), and large deletions and a duplication are indicated by a horizontal line linked to the appropriate type symbol. RECQL4 mutations identified in Rothmund–Thmonson, RAPADILINO or Baller–Gerold syndrome patients are further indicated by the symbol fill, with the key to the lower right.

Fig. 3

DNA metabolic activities of human RECQ helicases. Activities of human RECQ helicases on model DNA substrates is depicted, and can be thought of as different combinations of unwinding, translocation/displacement, strand annealing and, in the case of WRN exonucleolytic degradation activities. Different human RECQ helicases encode different combinations of the activities shown (see text for detail). The flag symbol on DNA strands provides a reference point to aid visualization of the consequences of RECQ-mediated biochemical activities.

Fig. 4

Inferred RECQ helicase substrates and their roles in DNA metabolism. The common model substrates depicted in Fig. 3 and used to define RECQ helicase biochemical activities have direct counterparts in cellular DNA metabolism. RECQ helicases are able to unwind and release DNA flaps (upper left); promote replication fork progression, regression or remodeling (lower left); release an invading 3′ DNA tail in a D-loop (upper right); and branch migrate and, in the case of BLM in conjunction with topoisomerase IIIα, resolve separate DNA duplexes joined in a Holiday junction (lower right).

Fig. 5

Pathogenesis of human RECQ helicase deficiency syndromes. A model is depicted that summarizes cellular and organismal consequences of loss of RECQ helicase function during and after development. Heritable loss of RECQ function leads to altered DNA metabolism in most or all cell lineages during and after development. Altered or aberrant DNA metabolism, in turn, leads to genetic instability, epigenetic ‘drift’ and cell loss or senescence that over time may compromise tissue structure and function while promoting the emergence of cells with a proliferative advantage to form specific neoplasms (upper right). Tumor generation is strongest in BS. Loss of WRN function also strongly promotes cellular senescence that contributes to global progeroid changes and may provide a non-specific tumor suppressive mechanism that limits tumor formation to a few susceptible cell lineages such as osteoblasts.