Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis

Abstract

The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair-deficient tumors with drugs that take advantage of the fundamental differences between normal repair-proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132-7. Ó2016 AACR.

Excess growth hormone suppresses DNA damage repair in epithelial cells

“…Either upregulated or downregulated/mutated DDR proteins are associated with metastasis (73). Thus, p53 downregulation or mutation induces epithelial mesenchymal transition, migration, and invasion and also inhibits p63, resulting in increased trafficking of β1-integrin, which is intimately involved in metastasis in human breast and prostate carcinomas (74,75).…”

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

“…2 Key proteins that signal DNA damage to cell-cycle checkpoints and DNA repair pathways include ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR), and DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) kinases (Fig 1). [3][4][5][6][7] The triggered response pathways may involve any of the repair mechanisms, including (1) base excision repair for single-strand breaks (SSBs), (2) nucleotide excision repair for repair of bulky adducts, (3) mismatch repair for mispaired bases, (4) homologous recombination repair (HRR) for double-strand breaks (DSBs) and intrastrand/interstrand crosslinks, (5) nonhomologous end joining (NHEJ) for DSB repair via direct religation of the ends, or (6) microhomology-mediated end joining (MMEJ) for repairing DSBs (Fig 1). 8 If the DNA damage is too severe or the lesion is irreparable, DDR checkpoints may trigger apoptosis.…”

Musashiexpression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival inDrosophila

“…Organisms have developed several DNA error correction mechanisms, as the inability to correct DNA errors leads to permanent cellular damage [16][17][18][19]. To prevent the propagation of DNA damage and improve survival following iradiation, cells choose from among several fates: cells may apoptose [26], enter a state of replicative arrest, such as senescence, or be cleared by phagocytosis or autophagy.…”