RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies

Abstract

Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2—mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies.

RAD52: Viral Friend or Foe?

“…Superficially, one might not predict that an error-prone process would even exist, let alone be evolutionarily preferred, but, counter-intuitively, C-NHEJ is indeed the major pathway of DSB repair for human cells. Ironically, tumor cells that are defective for HDR (see below) are forced to rely solely on mutagenic NHEJ pathways to maintain genome integrity and, because of this, these cells now show increased sensitivity to chemo [9,10] and synthetic-lethality-based therapies [11][12][13]. Importantly, there is no evidence to suggest that RAD52 plays any role in C-NHEJ.…”

“…Because of this reaction mechanism, A-NHEJ perforce always causes small deletions. A-NHEJ is partially dependent upon RAD52 [16], possibly due to the requirement for strand annealing, which is RAD52's seminal activity [12,13,17]. Alternative-NHEJ (A-NHEJ) is a more recently described pathway [14] where the mechanism is less well understood ( Figure 1B).…”

“…In the past decade, however, research on RAD52 has been buoyed and reenergized by studies implicating RAD52 in a wide variety of DNA metabolic reactions. Due to RAD52's popularity, the reader is directed to any number of recent, comprehensive reviews for specifics on RAD52's abundant purported activities [12,13,17]. For the sake of this review, we will focus predominately on one of these activities: BIR.…”

“…Viruses have historically evolved a myriad of mechanisms in which they either conscript cellular factors or, more frequently, inactivate them as a means to enable their own replication and survival. Recent data suggests that Adeno-Associated Virus (AAV) may replicate its DNA in a BIR-like fashion and/or utilize RAD52 to facilitate viral transduction and, as such, likely conscripts/requires the host RAD52 protein to promote its perpetuation.Cancers 2020, 12, 399 2 of 11 genome integrity and, because of this, these cells now show increased sensitivity to chemo [9,10] and synthetic-lethality-based therapies [11][12][13]. Importantly, there is no evidence to suggest that RAD52 plays any role in C-NHEJ.…”

“…Cancers 2020, 12, 399 2 of 11 genome integrity and, because of this, these cells now show increased sensitivity to chemo [9,10] and synthetic-lethality-based therapies [11][12][13]. Importantly, there is no evidence to suggest that RAD52 plays any role in C-NHEJ.…”