Abstract
DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.
Highlights
DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage
DNA repair defects underlined by BRCA1/2 deficiency and chromosomal translocations will be considered in the subsequent sections
This especially concerns discrimination between crossover and non-crossover products. The latter may result from homologous recombination repair (HRR), B-non-homologous end joining (NHEJ), or Single-strand annealing (SSA)
Summary
DNA double-strand breaks (DSBs) are, along with interstrand-crosslinks (ICLs), the most serious kind of DNA damage, and may result in chromosome breaks leading to chromosomal translocation, production of fusion genes, often displaying oncogenic properties to fuel cancer transformation [1]. DNA damage response (DDR), a complex multi-protein, evolutionary conserved cellular reaction to DNA damage is best known in the context of DSBs challenge (reviewed in [6]) It is initiated by the activation of the ATM Humans and other higher organisms repair DSBs primarily by non-homologous end joining (NHEJ) and homologous recombination repair (HRR) Another DSBR pathway is single-strand annealing (SSA), but it seems to be of a minor significance compared with NHEJ and HRR (reviewed in [8]). Homologous recombination repair may proceed according to the classical model of homologous recombination (HR) based on DSB repair and double Holliday junction resolution or take the form of SDSA (synthesis-dependent strand annealing) or BIR (break-induced replication). Updated information on the involvement of SSA in cancer transformation and therapy is presented
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