Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells

Abstract

Double-strand breaks occur during DNA replication and are also induced by ionizing radiation. There are at least two pathways which can repair such breaks: non-homologous end joining and homologous recombination (HR). Although these pathways are essentially independent of one another, it is possible that the proteins Mre11, Rad50 and Xrs2 are involved in both pathways in Saccharomyces cerevisiae. In vertebrate cells, little is known about the exact function of the Mre11-Rad50-Nbs1 complex in the repair of double-strand breaks because Mre11- and Rad50-null mutations are lethal. Here we show that Nbs1 is essential for HR-mediated repair in higher vertebrate cells. The disruption of Nbs1 reduces gene conversion and sister chromatid exchanges, similar to other HR-deficient mutants. In fact, a site-specific double-strand break repair assay showed a notable reduction of HR events following generation of such breaks in Nbs1-disrupted cells. The rare recombinants observed in the Nbs1-disrupted cells were frequently found to have aberrant structures, which possibly arise from unusual crossover events, suggesting that the Nbs1 complex might be required to process recombination intermediates.

Deficient DNA repair in the human progeroid disorder, Werner syndrome

“…Recent in vivo data suggest that WRN participates in late stages of HR resolution [16,17]. This is supported by the observation that WRN interacts functionally with Nbs1 [9] as Nbs1 is thought to function downstream of Rad51 [18].…”

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

“…It is tempting to speculate that BRCA1 is involved in the response to DSB or stalled replication forks and directs the subsequent recruitment of repair proteins, either MRN or BRCA2/Rad51. Although it is not clear whether the MRN complex is involved in homologous recombination in human cells, it has been suggested that the MRN complex might function in the resolution of stalled replication forks (39) and Nijmegen breakage syndrome gene 1 was reported to facilitate homologous recombination in DT40 cells (40). Disruption of the Nijmegen breakage syndrome gene 1 gene led to reduced gene conversion and sister chromatid exchanges, but the formation of Rad51 foci induced by g-radiation (6 Gy) was not affected.…”

Nibrin functions in Ig class-switch recombination

“…Nijmegen breakage syndrome ͉ B lymphocytes ͉ DNA repair T he nuclear complex of Mre11, Rad50, and nibrin (also known as Nbs1 or p95) is relevant for chromosomal stability, meiotic recombination, and telomere maintenance in eukaryotic cells (1)(2)(3), and the targeted inactivation of Mre11 (4), Rad50 (5), or nibrin (3) causes embryonic lethality in the mouse. In humans, two related chromosome instability disorders, Nijmegen breakage syndrome (NBS) and Ataxia-Telangiectasia-like disorder (ATLD) are caused by mutation of the genes encoding nibrin and Mre11, respectively.…”