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

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

doi:10.1038/s41421-019-0116-8

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

Cell Discov. 2019 Nov 5:5:47. doi: 10.1038/s41421-019-0116-8. eCollection 2019.

Authors

Yangyang Yu¹, Wenwen Jia^{1

2}, Yao Lyu¹, Dingwen Su¹, Mingliang Bai¹, Junwei Shen¹, Jing Qiao¹, Tong Han³, Wenqiang Liu¹, Jiayu Chen¹, Wen Chen¹, Dan Ye¹, Xudong Guo¹, Songcheng Zhu¹, Jiajie Xi¹, Ruixin Zhu¹, Xiaoping Wan³, Shaorong Gao¹, Jiyue Zhu⁴, Jiuhong Kang^{1

2}

Affiliations

¹ 1Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science; School of Life Sciences and Technology, Tongji University, Shanghai, 200092 China.
² 2Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123 China.
³ 3Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204 P. R. China.
⁴ 4Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210 USA.

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.

Keywords: Embryonic stem cells; Telomeres.

Grants and funding

R01 GM071725/GM/NIGMS NIH HHS/United States