The two faces of DNA repair: disease and therapy

Abstract

Our genome is the blueprint for our bodies. A number of sophisticated mechanisms help protect our genome from life-threatening cellular mistakes and environmental insults. Much current research focuses on understanding these mechanisms, how they prevent disease, and whether they can be targeted for therapeutic purposes. Here, we review the main mechanisms maintaining genome integrity, how their malfunctioning results in disease, and the exciting progress toward targeting these mechanisms for cancer treatments.

Figure 1

Top) Common endogenous and exogenous agents which generate different types of DNA lesions throughout the genome. Bottom) Mechanisms required for the repair of the different types of DNA lesions. Base-excision repair (BER) and nucleotide-excision repair (NER) are two mechanisms used to repair DNA single-strand breaks. HR, Homologous Recombination; NHEJ, non-homologous end-joining. 14-mer duplex DNA structure (pdb: 2M2C).

Figure 2

A) Main double-strand break repair pathways. NHEJ directly seals the broken DNA ends and occurs primarily during the G1 phase of the cell cycle. HR is a high-fidelity repair mechanism that occurs primarily during the S and G2 phases of the cell cycle and requires the information contained in the sister chromatid. The figure on the right schematically shows a replication fork with a double-strand break on one of the strands. B) Schematic model for the HR mechanism. 1) A double-strand break is present on the DNA template. 2) HR is initiated by resection of a double-strand break to provide 3′ single-stranded DNA overhangs. 3) Strand invasion by these 3′ single-stranded DNA overhangs into a homologous sequence is followed by DNA synthesis at the invading end. 4) The second double-strand break end is captured to form an intermediate with two Holliday junctions (HJs). The structure is resolved at the HJs in non-crossover or crossover products by specific HJ resolvases (black and grey arrow heads).

Figure 3

A) Schematic model for the mechanism of replication fork reversal and restart upon TOP1 inhibition. The DNA replication fork is schematically shown in the white circle that represents the cell nucleus. TOP1 inhibitors trap TOP1 on the nicked DNA intermediate, thereby preventing repair of the ssDNA lesion, and causing the replication forks to reverse. RECQ1 is required to restart the replication forks reversed by TOP1 inhibition. PARP1 prevents premature restart of the reversed forks by inhibiting RECQ1 activity (for more details see 20). B) Balance between DNA repair mechanisms of homologous recombination and non-homologous end-joining is important for genome stability. BRCA1 promotes HR and 53BP1 facilitates NHEJ. Loss of either BRCA1 or 53BP1 causes genomic instability and cancer predisposition, while loss of both ameliorates the phenotype. Recent studies showed that cancer cells deficient in BRCA1 lose 53BP1 to survive and resist therapy.