Targeting the DNA repair defect of BRCA tumours
Introduction
Women with germ-line heterozygous mutations in BRCA1 or BRCA2 are at elevated risk of developing breast (up to 85% in multi-case families), ovarian and other cancers [1]. BRCA1 appears to have a broad cellular role, having been implicated in a variety of cellular processes such as DNA repair, cell-cycle regulation, transcriptional regulation and chromatin remodelling. By contrast, functions ascribed to BRCA2 have largely been limited to DNA recombination and repair processes; the protein is of particular importance in the regulation of RAD51 activity, a highly conserved DNA recombinase involved in the repair of double-strand breaks and arrested replication forks [2, 3]. However, BRCA2 has recently been linked to cytokinesis and this could also, in part, explain the frequent aneuploidy observed in BRCA2-deficient cancers [4].
Cells that lack BRCA1 or BRCA2 have a deficiency in the repair of DNA double-strand breaks (DSBs) by the conservative, potentially error-free, mechanism of homologous recombination (HR) by gene conversion (Figure 1) [5, 6, 7]. This deficiency results in the repair of these DNA lesions by non-conservative, potentially mutagenic, mechanisms such as non-homologous end joining (NHEJ) and single strand annealing (SSA). The resulting genomic instability probably underlies the cancer predisposition caused by loss-of-function mutations in BRCA1 or BRCA2 [2, 3]. This review focuses on the shared role of BRCA1 and BRCA2 in homologous recombination-based DNA repair, the recent advances in our understanding of how this DNA repair defect can be targeted for tumour therapy, and the potential applicability of these approaches to sporadic as well as hereditary cancer.
Section snippets
Role of BRCA1 and BRCA2 in DNA repair
HR is a potentially error-free mechanism of repairing DNA DSBs, utilizing an identical sequence to copy and replace damaged DNA (Figure 1). The preferred template for HR is the identical sister chromatid, which is held in close proximity following replication by the cohesin proteins, facilitating location of the corresponding identical sequence following a DSB [8]. Alternative sequences on the same or other chromosomes can also act as templates for HR. To avoid potentially non-conservative
The Fanconi connection and complexities in HR
Although generally represented as a single linear pathway, recent results suggest that HR-based DNA repair is actually composed of a set of interrelated lesion-specific DNA repair pathways that make variable use of the central core HR machinery.
Detailed understanding of one of these specific pathways has come from the study of genes involved in Fanconi anemia (FA), a rare recessive disease characterised by developmental abnormalities, progressive bone marrow failure and a greatly increased risk
Targeted DNA damage
Tumours arising in carriers of heterozygous germline mutations in BRCA1 or BRCA2 gene have generally lost the wild-type allele and, therefore, do not express functional protein. Although a haplo-insufficiency phenotype does remain a formal possibility for BRCA1 or BRCA2, the majority of evidence suggests that this is not the case at least for DNA repair functions [31]. Therefore, loss-of-function of the HR pathway is restricted to the tumour, providing an ideal target for treatment.
BRCAness in sporadic cancers?
Although mutations in the BRCA1 or BRCA2 gene are rare in sporadic cancers, increasing evidence suggests that the BRCA and FA pathways may be inactivated by multiple mechanisms in a substantial proportion of sporadic cancers, and that these cancers could display ‘BRCAness’ [41•]. Potential mechanisms of pathway disruption include BRCA1 promoter methylation [42, 43], methylation of the FA gene FANCF [44•], and amplification of a novel gene, EMSY, the protein product of which interacts with BRCA2
Conclusions
Knowledge gained from the study of the BRCA1 and BRCA2 genes has considerable potential to impact both the targeted application of current chemotherapy drugs and the development of novel targeted therapies. To gain the highest therapeutic ratio in treating these tumours, DNA damage needs to be targeted to specific lesions that are reliant on the BRCA/Fanconi pathways for repair. The greatest challenge will be in the identification of sporadic cancers that might also benefit from the application
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work in our laboratory is funded by Breakthrough Breast Cancer Research and Cancer Research UK.
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