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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.

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