イシズ　アヤコ   Ishizu Ayako   石津　綾子    所属   医学部 医学科    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
掲載誌名	正式名：British journal of haematology 略　 称：Br J Haematol ISSNコード：13652141/00071048
掲載区分	国外
巻・号・頁	185(5),pp.888-902
著者・共著者	Matsumura Takayoshi, Nakamura-Ishizu Ayako, Takaoka Kensuke, Maki Hiroaki, Muddineni Siva S N A, Wang Chelsia Q, Suzushima Hitoshi, Kawakita Makoto, Asou Norio, Matsuoka Masao, Kurokawa Mineo, Osato Motomi, Suda Toshio
発行年月	2019/06
概要	Inherited thrombocytopenia is a genetically heterogeneous disease characterized by varying degrees of thrombocytopenia and risk of haematological malignancy, and the genetic cause of many cases remains unknown. We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB1 variant, R251H. TUBB1 encodes the tubulin β-1 chain, a major component of microtubules abundant in megakaryocytes. Variant TUBB1 disrupted the normal assembly of microtubules and impaired proplatelet formation in vitro. In addition, DNA damage response was severely attenuated by loss of TUBB1. We found that the nuclear accumulation of p53 (also termed TP53) and the expression of pro-apoptotic genes triggered by genotoxic stress were blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB1. Thus, we have demonstrated that microtubule dysfunction confers resistance to apoptosis, even in DNA damage-accumulated cells, which explains genome instability in the affected individuals. These studies will lead us to a better understanding of how microtubule dysfunction can contribute to the accumulation of DNA damage, genetic instability and leukaemogenesis.
DOI	10.1111/bjh.15835
PMID	30854628