An overview of RecQ helicases and related diseases

Abstract

RecQ helicases are known as "caretakers" of the genome for their conserved helicase activities to resolve different complex DNA structures. Aberrant accumulation of unsolved DNA structures could lead to defects in DNA replication, gene transcription, and unrepaired DNA lesions. Pathogenic mutations on BLM, WRN, and RECQL4 are associated with several pathological conditions, namely Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS). These syndromes are characterized by genomic instability and cancer predisposition. Additionally, some RecQ helicase diseases are linked to developmental defects and premature aging. In this review, we provide an overview of the RecQ helicases, focusing on the molecular functions and mechanisms, as well as the consequences of their dysfunction in cellular processes. We also discuss the significance of RecQ helicases in preventing various genetic disorders (BS, WS, RTS) and the insights obtained from the different animal models developed for studying the pathophysiology of RecQ helicase deficiencies.

Keywords: DNA repair; RecQ helicase; accelerated aging; cellular senescence; maintenance of genome stability.

Figure 1

The RecQ helicase family in human. The RecQ helicase family contains five members in humans. The helicase core containing a DEAD-/DEXH-/DEAH-like helicase (red box) and a C-terminal helicase domain (pink box) is conserved in all of the family members. The RQC domain (yellow box) is present in RECQL, BLM and WRN helicases. The HRDC domain (green box) is found in BLM and WRN only. The zinc-binding domain (blue box) is conserved in RECQL, BLM, WRN, and RECQL5. The exonuclease domain (purple grey box) is unique to WRN, whereas the N-terminal domain (light blue) is unique to BLM, and the mitochondrial localization sequence (brown box) is unique to RECQL4. Image is created by Illustrator for Biological Sequences (IBS) 2.0.

Figure 2

Conceptual framework illustrating how loss of WRN leads to the hallmarks of aging. Loss of WRN helicase results in alterations in different cellular and molecular processes (circles in the inner zone). These processes are linked to the known hallmarks of aging (circles in the outer zone) [173]. For instance, impaired DNA repair is associated with genome instability, whereas reduced proliferation and premature senescence are connected to stem cell exhaustion.