Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

Yi Liu,Feng Liu,Yizhao Cao,Huimin Xu,Yangxiu Wu,Su Wu,Dan Liu,Yong Zhao,Zhou Songyang,Wenbin Ma

doi:10.1016/j.celrep.2018.01.057

Yi Liu, Feng Liu + Show 8 more

Open Access

https://doi.org/10.1016/j.celrep.2018.01.057

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Abstract

Shwachman-Diamond syndrome (SDS) is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS) gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening. We found that overexpression of disease-associated SBDS mutants or knockdown of SBDS hampered the recruitment of telomerase onto telomeres, while the overall reverse transcriptase activity of telomerase remained unaffected. Moreover, we show that SBDS could specifically bind to TPP1 during the Sphase of cell cycle, likely functioning as a stabilizer for TPP1-telomerase interaction. Our findings suggest that SBDS is a telomere-protecting protein that participates in regulating telomerase recruitment.

Highlights

The Shwachman-Diamond syndrome (SDS), characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities, is a rare inherited autosomal recessive disease, with $90% of the patients harboring inheritable mutations of the Shwachman-Bodian-Diamond syndrome (SBDS) gene at chromosome 7q11 (Myers et al, 1993; Myers et al, 2013; Popovic et al, 2002)
We found that deficiency or disease-associated mutations of SBDS led to telomere shortening, and we demonstrate that SBDS is a TPP1-interacting protein that facilitates telomerase recruitment
Knockdown of SBDS led to severe cell growth defects, and cell cycle profile analysis showed S and G2/M phase delays in SBDS knockdown cells (Figure S1)

Summary

Introduction

The Shwachman-Diamond syndrome (SDS), characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities, is a rare inherited autosomal recessive disease, with $90% of the patients harboring inheritable mutations of the Shwachman-Bodian-Diamond syndrome (SBDS) gene at chromosome 7q11 (Myers et al, 1993; Myers et al, 2013; Popovic et al, 2002). The majority of SBDS gene mutations lead to truncated SBDS proteins (Boocock et al, 2003; Nakashima et al, 2004). Two of the most frequent diseaseassociated mutations are 183-184TA/CT and 258+2T/C, which result in two premature SBDS-truncated proteins with an in-frame stop codon (K62X) and a frameshift mutation (84Cfs3), respectively (Boocock et al, 2003). Previous reports suggest that SBDS may contribute to telomere regulation, because SDS and SBDS-mutated aplastic anemia (AA) patients have shorter telomeres (Calado et al, 2007; Thornley et al, 2002). The underlying mechanisms of how mutations in the SBDS gene lead to telomere shortening are not yet understood (Dokal and Vulliamy, 2010)

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