Guarding chromosomes from oxidative DNA damage to the very end

Abstract

The ends of each chromosome are capped by the telomere assembly to protect chromosomal integrity from telomere attrition and DNA damage. In response to DNA damage, DNA repair factors are enriched at damage sites by a sophisticated signaling and recruitment cascade. However, DNA damage response at telomeres is different from non-telomeric region of genomic DNA due to specialized sequences and structures of the telomeres. In the course of normal DNA replication or DNA damage repair, both the telomere shelterin protein complex and the condensed telomeric chromatin structure in mammalian cells are modified to protect telomeres from exposing free DNA ends which are subject to both telemere shortening and chromosome end fusion. Initiation of either homologous recombination or non-homologous end joint repair at telomeres requires disassembling and/or post-translational modifications of the shelterin complex and telomeric chromatin. In addition, cancer cells utilize distinct mechanisms to maintain telomere length and cell survival upon damage. In this review, we summarize current studies that focus on telomere end protection and telomere DNA repair using different methodologies to model telomere DNA damage and disruption. These include genetic ablation of sheltering proteins, targeting endonuclease to telomeres, and delivering oxidative damage directly. These different approaches, when combined, offer better understanding of the mechanistic differences in DNA damage response between telomeric and genomic DNA, which will provide new hope to identify potential cancer therapeutic targets to curtail cancer cell proliferation via induction of telomere dysfunctions.

Keywords: KillerRed; oxidative DNA damage; recombination; shelterin; telomere.

Figure 1.

DNA damage response at telomeres and chromosome sites in somatic cells and cancer cells  (A) Telomeric DNA damage response in normal cells. Cells consistently lose telomeres with each replication cycle and/or with the exposure to endogenous and exogenous DNA damages. Upon DNA damage, repair proteins are recruited to damaged telomeres, which also serve as signals for the activation of the cell cycle checkpoint mechanism rather than initiation of impropriate repair leading to chromosomal fusions. The persistent cell cycle arrest transits the cells into senescence. The deficiencies of p53 or Rb genes antagonize cell cycle arrest, leading to cell death or cancerous transformation. Cells that undergo ‘telomere crisis’ exhibit short telomeres or chromosomal fusions. (B) DNA damage response at non-telomeric regions. A subsequent DNA repair pathways including base-excision repair (BER), single-strand break repair (SSBR), HR, and NHEJ and the sequential DNA damage signal cascade are activated at sites of DNA damage. (C) Telomere maintenance in cancer cells. About 80% cancer cells express telomerase and 15% cancer cells use ALT pathway for telomere maintenance. Telomerase catalyzes the elongation of the telomeres and inhibits the DNA damage signals. Cancer cells utilize ALT pathway to prevent telomere shortening characterized by heterogeneous telomere lengths. ALT cancer cells are resistant to NHEJ in response to telomeric DNA damage, but show frequent recruitments of HR proteins at telomeres.