ABSTRACT
The human genome is continuously subject to a variety of genotoxic insults from endogenous sources, such as DNA replication errors, spontaneous deamination of cytosine and oxygen radicals formed as part of normal metabolism, as well as exogenous sources, such as chemical mutagens in the diet or atmosphere and ultraviolet radiation. Therefore, all living organisms have, of necessity, evolved a variety of unique and overlapping or complementary pathways to signal the damage to either cell cycle checkpoints and DNA repair or, if the damage is too great, then to cell death pathways. These DNA damage detection and repair pathways essentially behave as tumor suppressors and their defects can enable tumorigenesis in the presence of ongoing genotoxic stress. There are several pathways of DNA repair that are responsible for the repair of different types of lesions (see Chapter 1). There are pathways that repair damage on one strand of the DNA: the base excision repair/single strand break repair (BER/SSBR) pathway corrects damaged bases and single strand nicks (see Chapter 8), and the nucleotide excision repair (NER) pathway removes more bulky damage (see Chapter 9). DNA double strand breaks (DSBs) are repaired primarily by
Professor of Experimental Cancer Therapeutics, Newcastle University, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Email: nicola.curtin@ncl.ac.uk
non-homologous end joining (NHEJ) or homologous recombination (HR), depending on the cell cycle phase (HR requires a complimentary sister chromatid to act as template so, by defi nition can only take place during late S/G2) (see Chapter 14). DNA mismatch repair (MMR) is involved in the detection and repair of base mismatches, insertions and deletions that arise due to errors during replication (see Chapter 7).
