Human RecQ helicases in DNA repair, recombination, and replication

Abstract

RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.

Keywords: BLM; RECQL1; RECQL4; RECQL5; WRN; genome stability.

Figure 1

RecQ helicase protein family. (a) The domain structure of RecQ helicases from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens. Homologous domains are represented with solid-color boxes outlined with solid lines; the tentatively assigned zinc and RQC domains of RECQL4 are represented by rectangles outlined with dotted lines. (b) The helicase domains of human RECQL1, based on Protein Data Bank (PDB) identifier 2WWY (24). The structure includes two RecA-like domains, helicase domains 1 [HD1 (red )] and 2 [HD2 (blue)], and an ATP-binding cleft. The conserved helicase motifs are in yellow, and the aromatic loop is in pink. (c) The truncated RECQL1 bound to DNA is based on PDB 2WWY. The RQC domain is in purple, the β-hairpin is in green, and the DNA is in black. Abbreviation: aa, amino acid.

Figure 2

Protein–protein interactions among the RecQ helicases. The vertical panel to the left lists six DNA metabolic pathways and the RecQ helicases that participate in those pathways. Each RecQ helicase is represented as a colored hexagon. The interacting proteins are shown next to each RecQ helicase. Proteins that interact with four or five RecQ helicases are represented by light blue ovals, and proteins that interact with two or more RecQ helicases are represented by white ovals. Abbreviations: BER, base excision repair; DSBR, double-strand break repair; mRNA, messenger RNA; Topo, topoisomerase.

Figure 3

RecQ helicases in base excision repair (BER) and double-strand break repair (DSBR). (a) Summary of the BER pathway. Interactions between RecQ helicases and BER proteins are depicted by a green arrow (for activation) or a red bar (for inhibition). Asterisks after PARP1 and XRCC1 indicate that these genes are specifically downregulated by RECQL5 loss. The brown RecQ hexagon indicates that multiple RecQs interact with these proteins. (b) Summary of DSBR pathways. (i ) Nonhomologous end joining (NHEJ). (ii ) Homologous recombination (HR). (iii ) Alternative (Alt)-NHEJ. The involvement of RecQ helicases in DSBR is depicted. Each RecQ helicase is represented as a colored hexagon. The colored hexagons are consistent with the coloring in Figure 2. Other key proteins are shown as white ovals. DNA molecules are shown as blue/red or light blue/red duplexes. Dashed lines denote nascent DNA synthesis. Abbreviations: dHJ, double Holliday junction; dRP, deoxyribose phosphate; IR, ionizing radiation; MPG, methylpurine DNA glycosylase; P, 3′-phosphate; PCNA, proliferating cell nuclear antigen; Pol, DNA polymerase; RFC, replication factor C; SDSA, synthesis-dependent strand annealing; Topo, topoisomerase; UA, 3′-α,β unsaturated aldehyde; UNG, uracil DNA glycosylase.

Figure 4

RecQ helicases in DNA replication. Putative roles of RecQ helicases during initiation of DNA replication, Okazaki fragment processing, leading- and lagging-strand elongation, fork restart, and regression are indicated. The orange star and triangle denote polymerase blocking DNA damage. In addition, RECQL5 may specifically inhibit transcription to prevent replication and transcription fork collisions. Abbreviations: RQ1, RECQL1 helicase; RQ4, RECQL4 helicase; RQ5, RECQL5 helicase.

Figure 5

RecQ helicases (BLM, WRN, and RECQL4) in telomere maintenance and repair. Interactions with shelterin proteins (TRF1, TRF2, and POT1) and resolution of secondary structures that are potential barriers to telomere replication are shown. RecQs may resolve inter- and intratelomeric substrates, G quadruplexes (G4s), and telomeric T-loops and D-loops. Abbreviations: BIR, break-induced replication; HJ, Holliday junction; RPA, replication protein A; RQ4, RECQL4; TIN2, TRF1-interacting nuclear factor 2; TPP1, POT1-interacting telomere end–binding protein.

Figure 6

Interactions between RecQ helicases. (a) Human RecQ helicases can play both overlapping and nonredundant roles. They can cooperate with each other functionally and complement each other in certain DNA metabolic pathways. (b) The predominant role of each RecQ helicase in each DNA metabolic pathway is indicated. Larger, bold font equates to greater predominance for the role of a specific enzyme in a specific pathway.