The Telomere Deprotection Response Is Functionally Distinct from the Genomic DNA Damage Response

Abstract

Summary Loss of chromosome end protection through telomere erosion is a hallmark of aging and senescence. Here we developed an experimental system that mimics physiological telomere deprotection in human cells and discovered that the telomere deprotection response is functionally distinct from the genomic DNA damage response. We found that unlike genomic breaks, deprotected telomeres that are recognized as DNA damage but remain in the fusion resistant intermediate-state activate differential ATM signaling where CHK2 is not phosphorylated. Also unlike genomic breaks, we found that deprotected telomeres do not contribute to the G2/M checkpoint and are instead passed through cell division to induce p53-dependent G1 arrest in the daughter cells. Telomere deprotection is therefore an epigenetic signal passed between cell generations to ensure that replication-associated telomere-dependent growth arrest occurs in stable diploid G1 phase cells before genome instability can occur.

Senescence from G2 arrest, revisited

“…28,49 Importantly, this work also provided evidence for the occurrence of 4N senescent cells in human melanocyte naevi, the first in vivo senescence model, 94 suggesting that the G2 exit program has a more general role in senescence. The results showing that mitotic bypass requires p53, as its absence leads to aberrant mitosis and cell death, corroborate the observations by the Karlseder team, 83 but they apparently contradict the finding that mitotic bypass in p53-deficient cells leads to endoreplication. 88 The most likely explanation is that the strong and persistent DNA damage signaling induced by POT1a/b double knockdown 88 causes sustained Chk1/2 activation that prevents Cdk1 activation (and mitosis), resulting in prolonged G2 arrest.…”

“…Furthermore, it is unclear to what extent this telomere-deprotection-DNA damage response actually contributes to replicative senescence because both Chk1 and Chk2 are activated by short telomeres, 34,87,81 whereas telomere erosion in aging fibroblasts activates mainly the G2/M checkpoint. 81 Another intriguing result is the absence of mitotic bypass and endoreplication in cells that lack p53 and that experience prolonged DNA damage signaling due to persistent loss of telomere protection, 83 which is in stark contrast with the results documented by the De Lange team 88 (see below).…”

“…83 Instead, after completion of mitosis, DNA damage induces p53-dependent cell cycle exit in G1. Why do intermediate-state telomeres not activate the checkpoint and block G2/M progression?…”

“…3). Conversely, transient Chk1/2 activation, induced by partial TRF2 depletion 83 or acute DNA damage (by IR), 93 in the absence of (efficient) p21 induction can transiently delay, but not prevent mitosis.…”

DNA Damage to a Single Chromosome End Delays Anaphase Onset

“…Cells with defective ATM or p53 escape from G 2 arrest and enter mitosis with persisting telomere dysfunction-induced foci on mitotic chromosomes (20). However, recent studies indicated that DDR is attenuated in mitosis compared with interphase (21)(22)(23), and thus cells may respond differently to telomere damage induced during mitosis (24). A recent study demonstrated that the forced mitotic arrest results in telomere uncapping with ␥-H2AX focus formation and ATM activation (25).…”