Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation

Yangyang Yu,Tong Han,Junwei Shen,Shifeng Zhu ,Wenqiang Liu,Xiaoping Wan,Shaorong Gao,Dan Ye,Wen Chen,Jiyue Zhu,Mingliang Bai,Yao Lyu,Xudong Guo,Wenwen Jia,Dingwen Su,Rong Zhu ,Jing Qiao,Jiajie Xi,Jiayu Chen,Jiuhong Kang

doi:10.1038/s41421-019-0116-8

Abstract

Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.

Highlights

Telomeres are special structures located at chromosomal ends
From the 56 ES clones screened, 10 Pwp1+/− cell lines were were passaged in the absence or presence of doxycycline (Dox). l Effect of Pwp[1] knockdown on telomere length in embryonic stem cell (ESC) as measured by quantitative fluorescence in situ hybridization (Q-FISH)
Cells were stained for telomeres (TTAGGG; red), shelterin (TRF1 (f) or TIN2 (h); green), and nuclei (Hoechst 33342; blue). g, i Quantifications of (f) and (h), respectively

Summary

Introduction

Telomeres are special structures located at chromosomal ends. They are composed of variable numbers of the simple DNA repeat TTAGGG, which is associated with large shelterin complex proteins[1]. This type of telomeric nucleoprotein structure is conserved in the majority of eukaryotic species. The variable numbers of telomeric DNA repeats result in differences in telomere length[2]. Elucidating the molecular mechanisms underlying the regulation of telomere length is important. The known mechanisms of telomere length regulation[5,6] are as follows: (1)

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Results

Conclusion