Single-Strand Annealing in Cancer

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.

RAD52: Paradigm of Synthetic Lethality and New Developments

“…Through its strand annealing and DNA pairing activities, RAD52 is central to the SSA and BIR pathways ( Gottifredi and Wiesmuller 2020 ). These alternative pathways are highly mutagenic and provide a conducive environment for chromosomal translocations to occur through non-specific, error-prone joining of two heterologous chromosomes ( Malkova and Ira 2013 ; Blasiak 2021 ). For example, the hyper-resection of DSB ends in the absence of DNA damage sensor proteins such as 53BP1, DNA-PKcs, and EXOSC10 in S/G 2 phase promotes mutagenic SSA activity ( Domingo-Prim et al, 2019 ; Mladenov et al, 2019 ; Toma et al, 2019 ; Morales et al, 2021 ).…”

RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair

“…Accumulating evidence suggests that the choice of DSBR pathway in replicating cells differs from that in their non-replicating counterpart (reviewed in [ 5 ]). Here, we limit our considerations to HRR and NHEJ as they are much more common than SSA [ 84 ].…”

A Simulated Shift Work Schedule Does Not Increase DNA Double-Strand Break Repair by NHEJ in the Drosophila Rr3 System

“…HRR templated from an intact sister chromatid during late S or G2 can restore the original sequence, whereas HRR from the homolog in a heterozygous individual will result in the loss of heterozygosity (gene conversion). DSBs flanked by repeated sequences may be repaired by annealing of the complementary sequences with loss of the intervening region, in a process called single-strand annealing (SSA) (reviewed in [ 33 ]). Non-homologous end-joining (NHEJ) DSB repair rejoins the ends directly, without consulting homologous sequence external to the break.…”