A rare polymorphic variant of NBS1 reduces DNA repair activity and elevates chromosomal instability.
Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia. This polymorphic variant is located in the N-terminal region that interacts with other DNA repair factors. In earlier work, we had identified a remarkable number of structural chromosomal aberrations in a patient with pediatric aplastic anemia with a homozygous polymorphic variant of NBS1-I171V; however, it was unclear whether this variant affected DSB repair activity or chromosomal instability. In this report, we demonstrate that NBS1-I171V reduces DSB repair activity through a loss of association with the DNA repair factor MDC1. Furthermore, we found that heterozygosity in this polymorphic variant was associated with breast cancer risk. Finally, we showed that this variant exerted a dominant-negative effect on wild-type NBS1, attenuating DSB repair efficiency and elevating chromosomal instability. Our findings offer evidence that the failure of DNA repair leading to chromosomal instability has a causal impact on the risk of breast cancer development.
Authors' Affiliations: Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute; Department of Medical Genome Sciences, Graduate School of Frontier Sciences; and.
Yuki
Y
Yamamoto
Authors' Affiliations: Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute;
Mamiko
M
Miyamoto
Authors' Affiliations: Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute; Institute of Microbial Chemistry (BIKAKEN), Tokyo; and.
Daisuke
D
Tatsuda
Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
Michiaki
M
Kubo
Authors' Affiliations: Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute;
Hitoshi
H
Nakagama
Human Genome Center Institute of Medical Science, The University of Tokyo;
Yusuke
Y
Nakamura
Department of Medical Genome Sciences, Graduate School of Frontier Sciences; and.
Hitoshi
H
Satoh
Human Genome Center Institute of Medical Science, The University of Tokyo;
Koichi
K
Matsuda
Department of Medical Genome Sciences, Graduate School of Frontier Sciences; and.
Toshiki
T
Watanabe
Authors' Affiliations: Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute; cota@ncc.go.jp.
Tsutomu
T
Ohta
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D016415:Sequence Alignment; D015534:Trans-Activators / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C413163:MDC1 protein, human; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators