Abstract
Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The C-terminus of NBS1 is essential for interactions with MRE11, a homologous recombination repair nuclease, and ATM, a key player in signal transduction after the generation of DNA double-strand breaks (DSBs), which is induced by IR. Moreover, NBS1 regulates chromatin remodeling during DSB repair by histone H2B ubiquitination through binding to RNF20 at the C-terminus. Thus, NBS1 is considered as the first protein to be recruited to DSB sites, wherein it acts as a sensor or mediator of DSB damage responses. In addition to DSB response, we showed that NBS1 initiates Polη-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it also functions after the generation of interstrand crosslink DNA damage. Thus, NBS1 has multifunctional roles in response to DNA damage from a variety of genotoxic agents, including IR.
Highlights
Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by immunodeficiency, microcephaly, growth retardation, and a high frequency of malignancies [1]
In addition to double-strand breaks (DSBs) response, we showed that NBS1 initiates Pol-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it functions after the generation of interstrand crosslink DNA
Klement et al proposed a model in which decondensing heterochromatin at DSB sites required two events; first, CHD3.1 detaches from DSB sites through KAP-1 phosphorylation, and second, SNF2h is replaced with CHD3.1 by RNF20-dependent H2B ubiquitination [61]
Summary
Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by immunodeficiency, microcephaly, growth retardation, and a high frequency of malignancies [1]. Cells derived from patients with NBS exhibit high sensitivity to DNA-damaging agents, including ionizing radiation (IR), chromosome instability, and abnormal cell cycle checkpoints [2]. DSB signals are amplified and transduced to numerous downstream effectors, including p53 for cell cycle checkpoints, CHD3.1 for chromatin remodeling, and Rad for DSB repair machinery [12]. Fanconi anemia (FA) because the cells from this patient were sensitive to DNA interstrand crosslink (ICL) agents such as mitomycin-C; this feature is a hallmark of FA. This evidence suggests that NBS1 has multifunctional roles in response to DNA damage from a variety of genotoxic agents. We summarize the functional roles of NBS1 in response to ultraviolet (UV) and ICLs in addition to IR
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