Homologous Recombination and Its Role in Carcinogenesis

Abstract

Cancer develops when cells no longer follow their normal pattern of controlled growth. In the absence or disregard of such regulation, resulting from changes in their genetic makeup, these errant cells acquire a growth advantage, expanding into precancerous clones. Over the last decade, many studies have revealed the relevance of genomic mutation in this process, be it by misreplication, environmental damage, or a deficiency in repairing endogenous and exogenous damage. Here, we discuss homologous recombination as another mechanism that can result in a loss of heterozygosity or genetic rearrangements. Some of these genetic alterations may play a primary role in carcinogenesis, but they are more likely to be involved in secondary and subsequent steps of carcinogenesis by which recessive oncogenic mutations are revealed. Patients, whose cells display an increased frequency of recombination, also have an elevated frequency of cancer, further supporting the link between recombination and carcinogenesis.

Figure 1

Mechanisms of deletion. (a) Replication slippage, where DNA polymerase dissociates from its template and reanneals to homologous sequences nearby resulting in either a deletion (shown) or insertion (not shown) of sequences. These tend to be relatively small deletions or insertions and are usually in regions of repetitive DNA. (b) Intrachromosomal or intrachromatid deletion may be mediated by a number of different mechanisms, two of the most likely being a crossover event and single strand annealing. A crossover event is mediated by aligning homologous sequences, strand invasion, possibly following a single-stranded break, allows strand exchange and recombination between the two homologous sequences. The result is a deletion of the intervening sequences. Single strand annealing is another likely mechanism that requires a double strand break between the homologous sequences. A single strand exonuclease can degrade one strand at the DNA ends until homology is revealed allowing the broken ends to anneal and the intervening sequences to be clipped off. (c) Interchormatid deletion is most likely to result from an unequal crossover event, only occuring in G2 after the chromatid has been replicated but before they are segregated. Again, the event is mediated by a repeated region of homology, but in these events two products are formed, a deletion and a triplication on the two resultant recombinant chromosomes. (d) Interchromosomal deletion is similar to interchromatid deletion except that the interaction is between homologous chromosomes.