TUBB 1 dysfunction in inherited thrombocytopenia causes genome instability

• Published in: British journal of haematology Vol. 185; no. 5; pp. 888 - 902
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: 01.06.2019
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.15835

Summary 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 TUBB 1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB 1 variant, R251H. TUBB 1 encodes the tubulin β‐1 chain, a major component of microtubules abundant in megakaryocytes. Variant TUBB 1 disrupted the normal assembly of microtubules and impaired proplatelet formation in vitro . In addition, DNA damage response was severely attenuated by loss of TUBB 1. We found that the nuclear accumulation of p53 (also termed TP 53) and the expression of pro‐apoptotic genes triggered by genotoxic stress were blocked in TUBB 1‐deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB 1 . 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.