American Association for Cancer Research
00085472can133037-sup-fig2.pdf (303.64 kB)

Supplementary Figure 2 from A Rare Polymorphic Variant of NBS1 Reduces DNA Repair Activity and Elevates Chromosomal Instability

Download (303.64 kB)
journal contribution
posted on 2023-03-30, 22:21 authored by Yuki Yamamoto, Mamiko Miyamoto, Daisuke Tatsuda, Michiaki Kubo, Hitoshi Nakagama, Yusuke Nakamura, Hitoshi Satoh, Koichi Matsuda, Toshiki Watanabe, Tsutomu Ohta

PDF file - 302KB, Survival in response to AZD2281 and cell cycle arrest in other cells expressing an NBS1-I171V polymorphic variant.



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. Cancer Res; 74(14); 3707–15. ©2014 AACR.

Usage metrics

    Cancer Research



    Ref. manager