Abstract
RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund–Thomson syndrome (RTS), Baller–Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.
Highlights
Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, United States
double-strand break (DSB) are generated during endogenous events such as after the collapse of replication forks (Bouwman and Crosetto, 2018), SPO11-induced DSB formation during meiosis (Tock and Henderson, 2018), V(D)J recombination (Chi et al, 2020), and via reactive oxygen species generated during metabolism, as well as from various exogenous stresses which include ionizing radiation (IR) and cancer chemotherapeutic agents (Tubbs and Nussenzweig, 2017) (Figure 1)
To overcome severe consequences from DSBs, mammalian cells have evolved at least four pathways to repair this type of DNA lesion, termed non-homologous end joining (NHEJ), homologous recombination (HR), and the alternative end-joining pathways, microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA) (Figure 2)
Summary
Homologous recombination (HR) requires a homologous DNA sequence to serve as a template for DNA synthesisdependent repair. During SSA, the generated 3 ssDNAs are annealed by RAD52 via alignment of homologous sequences, whereas multiple enzymes are responsive for end bridging and annealing in MMEJ, including the MRN complex, PARP1, and Polθ (Sallmyr and Tomkinson, 2018). The non-complementary sequences generate 3 ssDNA overhangs that are removed by nucleases Both MMEJ and SSA complete with gap filling and DNA ligation by DNA polymerases and DNA ligases, but the exact enzymes and mechanisms that drive these processes are not well defined (Sallmyr and Tomkinson, 2018; Patterson-Fortin and D’Andrea, 2020). The repair of DSBs by MMEJ and SSA are intrinsically mutagenic as they cause deletions and rearrangements, resulting in genomic instability (Sallmyr and Tomkinson, 2018; Patterson-Fortin and D’Andrea, 2020)
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