Abstract
DNA Helicase B (HELB) is a conserved helicase in higher eukaryotes with roles in the initiation of DNA replication and in the DNA damage and replication stress responses. HELB is a predominately nuclear protein in G1 phase where it is involved in initiation of DNA replication through interactions with DNA topoisomerase 2-binding protein 1 (TOPBP1), cell division control protein 45 (CDC45), and DNA polymerase α-primase. HELB also inhibits homologous recombination by reducing long-range end resection. After phosphorylation by cyclin-dependent kinase 2 (CDK2) at the G1 to S transition, HELB is predominately localized to the cytosol. However, this cytosolic localization in S phase is not exclusive. HELB has been reported to localize to chromatin in response to replication stress and to localize to the common fragile sites 16D (FRA16D) and 3B (FRA3B) and the rare fragile site XA (FRAXA) in S phase. In addition, HELB is phosphorylated in response to ionizing radiation and has been shown to localize to chromatin in response to various types of DNA damage, suggesting it has a role in the DNA damage response.
Highlights
Expression in the nucleus was increased [3]. This mutant became inactive at increased temperatures, and the cells with inactive Helicase B (HELB) showed a decreased incidence of DNA replication compared to wild type cells the rate of elongation was unaffected [4]
Phosphorylation of S967 in the subcellular localization domain (SLD) domain by cyclin-dependent kinase 2 (CDK2) during the late G1 phase results in the the soluble nuclear fraction [10]. Both cyclin E/CDK2 and cyclin A/CDK2 were able to phosphorylate export of the majority of HELB to the cytoplasm during S phase [7], some HELB remains in HELB in vitro, but it was suggested that, due to the co-immunoprecipitation of cyclin E with HELB, the soluble nuclear fraction [10]
S phase, indicating that microinjected with wild‐type HELB in G1 phase progressed into S phase normally, whereas cells micro‐injected with HELB containing mutations in the Walker A or B motifs exhibited delayed entry into the S phase, indicating that HELB is required for timely cell cycle progression [2]
Summary
Helicases are vital to any event that requires the separation of the two strands of DNA or RNA such as DNA repair, replication and recombination. A heat sensitive mutant of HELB was first discovered in murine FM3A cells [4] When these cells were arrested in early S phase, HELB expression in the nucleus was increased [3]. This mutant became inactive at increased temperatures, and the cells with inactive HELB showed a decreased incidence of DNA replication compared to wild type cells the rate of elongation was unaffected [4]. This suggests that the helicase functions primarily in the early stages of S phase. HELB knockout mice are normal under unchallenged conditions [6], and the effects of endogenous replication stress on these mice are still unknown
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