Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

Abstract

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.

Germline mutation of MDM4 , a major p53 regulator, in a familial syndrome of defective telomere maintenance

“…This led us to compare TERRA transcripts in WT and Mdm4 TM/TM cells. Consistent with an earlier report (26), p53 activation led to increased TERRA at the mouse Xq subtelomeric region in WT cells ( fig. S3B).…”

“…S3A). Recently, in apparent contradiction with our finding that p53 activation can cause telomere shortening (5), p53 was proposed to prevent telomere DNA degradation by inducing subtelomeric transcripts, including telomere repeat-containing RNA (TERRA) (25,26), which suggested a complex, possibly context-dependent impact of p53 on telomeres (27). This led us to compare TERRA transcripts in WT and Mdm4 TM/TM cells.…”

DAXX-ATRX-H3.3 Regulation of p53 Chromatin Binding and DNA Damage Response

“…S1b). Consistent with our previous publication 18 , the bulk of telomere DNA signals reduced in both Ctrl and DAXX_KO cells treated with topoisomerase inhibitor etoposide. Telomere circles (t-circles) were observed in DAXX_KO cells by 2D agarose gel analysis, and their frequency was reduced by reintroduction of a wild-type (WT) DAXX transgene (Fig.…”

“…p53 is a DNA binding protein and master transcriptional regulator of genome integrity controlling transcription of gene networks for cellular senescence and apoptosis 15,16 . p53 binds to several loci within the cellular genome including promoters, enhancers, transcriptionally inactive regions as well as retrotransposon-like elements in many human subtelomeres 17,18 . The inter-relationship between DAXX-ATRX, and p53 DNA-damage response function in ALT is not completely understood.…”

Tumor suppressor p53: from engaging DNA to target gene regulation

“…The lack of traditional signifiers of transcriptional regulatory potential (such as particular histone modification patterns) might suggest these binding events are evolutionary remnants, could have context-dependent transcriptional roles, or could function in non-traditional roles. One possibility is that p53 might act locally to influence DNA repair and protect genome integrity, such as in the case where p53 binds to both human telomeres and other fragile genetic sites to influence chromatin structure that protects DNA from damage ( 64 , 162 ). Protection of these regions from DNA damage requires local p53-dependent transcription to establish the appropriate repressive heterochromatin features, but does not appear to require expression of any common p53 target gene.…”