Contributions of DNA interstrand cross-links to aging of cells and organisms

Abstract

Impaired DNA damage repair, especially deficient transcription-coupled nucleotide excision repair, leads to segmental progeroid syndromes in human patients as well as in rodent models. Furthermore, DNA double-strand break signalling has been pinpointed as a key inducer of cellular senescence. Several recent findings suggest that another DNA repair pathway, interstrand cross-link (ICL) repair, might also contribute to cell and organism aging. Therefore, we summarize and discuss here that (i) systemic administration of anti-cancer chemotherapeutics, in many cases DNA cross-linking drugs, induces premature progeroid frailty in long-term survivors; (ii) that ICL-inducing 8-methoxy-psoralen/UVA phototherapy leads to signs of premature skin aging as prominent long-term side effect and (iii) that mutated factors involved in ICL repair like ERCC1/XPF, the Fanconi anaemia proteins, WRN and SNEV lead to reduced replicative life span in vitro and segmental progeroid syndromes in vivo. However, since ICL-inducing drugs cause damage different from ICL and since all currently known ICL repair factors work in more than one pathway, further work will be needed to dissect the actual contribution of ICL damage to aging.

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

“…Our model with preferential oxidative damage of fibroblasts residing in the connective tissue of different organs may very well reflect the situation in patients subjected to ROS and DNA damage-inducing chemotherapy or radiotherapy (Grillari et al, 2007). While tissues with highly proliferative cells of epithelial origin mainly undergo apoptosis, connective tissue resident fibroblasts rather undergo a senescence programme with a metabolically changed phenotype, loss of tissue homoeostasis and aging.…”

“…While tissues with highly proliferative cells of epithelial origin mainly undergo apoptosis, connective tissue resident fibroblasts rather undergo a senescence programme with a metabolically changed phenotype, loss of tissue homoeostasis and aging. In fact, long-term survivors of chemotherapy and radiotherapy show evidence for premature aging (Grillari et al, 2007).…”

DNA double-strand breaks: A potential causative factor for mammalian aging?

“…Evidence for this possibility comes from human and mouse aging models that display similar phenotypes even though they are defective for different DNA repair pathways. For example, premature cellular senescence is observed for fibroblasts derived from aging models defective for NHEJ (Lim et al, 2000), ICL repair (Grillari et al, 2007) or telomere maintenance (Chin et al, 1999). Furthermore, NHEJ suppresses premature cellular senescence and apoptosis caused by exposure to a histone deacetylase inhibitor (Yaneva et al, 2005).…”

Limited Repair of Critical DNA Damage in Cells Exposed to Low Dose Radiation

“…ATR-dependent activation of the major FA-complex (A-C, E-G, L, and FAAP100) is the central event of repair of ICL that blocks the replication fork. The occurrence of ICL in the replication fork is recognized by several FA-protein complexes, including FANCM and FAAP24, which provide access of other proteins to the damage to repair it (Grillari et al, 2007;Dextraze et al, 2010). An important role in these events is played by the complex FANCI/FANCD2, which binds to DNA sites with ICL (Smogorzewska et al, 2010).…”