Priority Research Papers:
Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53
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Stephen Tutton1,2, Zhong Deng1, Nitish Gulve1, Olga Vladimirova1, Kate Beishline1,3, Andreas Wiedmer1, Maureen Murphy1 and Paul M. Lieberman1
1 The Wistar Institute, Philadelphia, PA, USA
2 Childrens Hospital of Philadelphia, Philadelphia, PA, USA
3 Bloomsburg University of Pennsylvania, Bloomsburg, PA, USA
|Paul M. Lieberman,||email:||[email protected]|
Keywords: TP53; telomere; TERRA; DNA damage; polymorphism
Received: March 22, 2019 Accepted: May 13, 2019 Published: June 04, 2019
Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.
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