The impact of oxidative DNA damage and stress on telomere homeostasis

Abstract

Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Because telomeres shorten progressively with each replication, they impose a functional limit on the number of times a cell can divide. Critically short telomeres trigger cellular senescence in normal cells, or genomic instability in pre-malignant cells, which contribute to numerous degenerative and aging-related diseases including cancer. Therefore, a detailed understanding of the mechanisms of telomere loss and preservation is important for human health. Numerous studies have shown that oxidative stress is associated with accelerated telomere shortening and dysfunction. Oxidative stress caused by inflammation, intrinsic cell factors or environmental exposures, contributes to the pathogenesis of many degenerative diseases and cancer. Here we review the studies demonstrating associations between oxidative stress and accelerated telomere attrition in human tissue, mice and cell culture, and discuss possible mechanisms and cellular pathways that protect telomeres from oxidative damage.

Keywords: Base excision repair; Oxidative DNA damage; Oxidative stress; Telomeres.

Figure 1

Diseases associated with oxidative stress, chronic inflammation and shortened telomeres. The schematic summarizes various diseases that are characterized by elevated reactive oxygen species as well as shortened average telomere lengths as measured either in white blood cells or in the affected/inflamed tissues, compared to unaffected individuals or tissues. See text for details and citations.

Figure 2

Consequences of replication fork stalling and blocks at telomeres. The schematic shows a model for how telomere fragility or telomere losses arise from DNA lesions that stall or block replication fork progression, respectively. DNA replication fork encounters with single strand breaks (SSBs) can cause the fork to collapse into a double strand break. Fragile telomeres manifest as multi-telomeric foci at a chromatid end, and are proposed to result from uncondensed regions arising from accumulated unreplicated ssDNA. Telomeres losses manifest as chromatid ends lacking sufficient telomeric DNA for detection with a telomeric probe. Telomerase can suppress telomere losses by extending a pre-maturely truncated telomere.

Figure 3

Processing of 8-oxoG. When 8-oxoG forms opposite C by direct oxidation (i), it is recognized by OGG1 (ii) which removes the modified base. OGG1 or APE1 then processes the abasic site to make it a suitable substrate for the remaining steps of BER. When dGTP is oxidized to 8-oxoGdTP (iii), and escapes degradation by MTH1, incorporation by telomerase results in termination of telomere synthesis (iv). If a DNA polymerase incorporates 8-oxodGTP opposite C and it escapes BER, a subsequent round of replication can result in incorporation of A opposite 8-oxoG (vi). MUTYH is able to excise the A, producing a gap filled in by Pol λ or Pol β, avoiding a G:T/C:A transversion mutation. Proteins in parentheses can stimulate OGG1 activity.

Figure 4

Models for 8-oxoG induced mutations at telomeres. A) The schematic shows three possible scenarios of 8-oxodGTP insertion opposite A during telomere replication and the resulting change in telomeric repeat sequence. B) If 8-oxoG forms directly in telomeric repeats, the misincorporation of dATP during telomere replication would alter the telomeric repeat to TTATGG, TTAGTG or TTAGGT depending on the lesion position. C) The variant GTAGGG repeat can arise if telomerase misincorporates 8-oxodGTP opposite rA during telomeric DNA synthesis, and the mispair is extended.