Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

Abstract

DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/ hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highlyconserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.

NKX3.1 contributes to S phase entry and regulates DNA damage response (DDR) in prostate cancer cell lines

“…These factors might have roles in maintaining genome stability [21][22][23][24]. We report that functional NKX3.1, the prostate-and testis-restricted homeoboxcontaining factor, activates DNA damage response upon topoisomerase I inhibition in prostate cells.…”

“…Androgen-responsive LNCaP cells (passage number [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] were propagated in RPMI1640 (Invitrogen, UK) medium supplemented with 10% heat-inactivated FBS (Invitrogen, UK). Cells were serum starved in the presence of 2% for 48 h and 0.5% for an additional 24 h in CT-FBS containing RPMI1640.…”

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

“…Ataxia telangiectasia, caused by defects in the ataxia telangiectasia mutated (ATM) gene, is prominent among these disorders, and is related to Nijmegen breakage syndrome (NBS) (Shiloh, 1997;Tauchi et al, 2002b). NBS is an autosomal recessive genetic disorder characterized by immunodeficiency, microcephaly, growth retardation and a high frequency of lymphoid malignancies (Tauchi et al, 2002b;Kobayashi et al, 2004).…”

“…Ataxia telangiectasia, caused by defects in the ataxia telangiectasia mutated (ATM) gene, is prominent among these disorders, and is related to Nijmegen breakage syndrome (NBS) (Shiloh, 1997;Tauchi et al, 2002b). NBS is an autosomal recessive genetic disorder characterized by immunodeficiency, microcephaly, growth retardation and a high frequency of lymphoid malignancies (Tauchi et al, 2002b;Kobayashi et al, 2004). Cells from NBS patients exhibit a highly elevated sensitivity to ionizing radiation (IR), chromosome instability and abnormal cell cycle checkpoints (Weemaes et al, 1981;Tauchi et al, 2002b;Kobayashi et al, 2004).…”

“…NBS is an autosomal recessive genetic disorder characterized by immunodeficiency, microcephaly, growth retardation and a high frequency of lymphoid malignancies (Tauchi et al, 2002b;Kobayashi et al, 2004). Cells from NBS patients exhibit a highly elevated sensitivity to ionizing radiation (IR), chromosome instability and abnormal cell cycle checkpoints (Weemaes et al, 1981;Tauchi et al, 2002b;Kobayashi et al, 2004). The gene mutated in NBS is NBS1 (NBN/Nibrin), which has been mapped to chromosome 8q21-24.…”