RAD52: Viral Friend or Foe?

Abstract

Mammalian Radiation Sensitive 52 (RAD52) is a gene whose scientific reputation has recently seen a strong resurgence. In the past decade, RAD52, which was thought to be dispensable for most DNA repair and recombination reactions in mammals, has been shown to be important for a bevy of DNA metabolic pathways. One of these processes is termed break-induced replication (BIR), a mechanism that can be used to re-start broken replication forks and to elongate the ends of chromosomes in telomerase-negative cells. 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.

Single-Strand Annealing in Cancer

“…In general, SSA seems to be a somehow “forgotten” or underestimated DSBR pathway in research, as several reports on synthetic lethality consider only HRR and NHEJ, including B-NHEJ, as DSBR pathways, and mention SSA as a likely operating system [ 115 , 116 ]. It is especially important in the context of the involvement of RAD52 in B-NHEJ and HRR [ 117 ].…”

“…Apart from repair, RAD52 is involved in many aspects of DNA and RNA metabolism, including replication, which are exploited by viruses to facilitate their propagation [ 117 , 122 ]. This naturally makes RAD52 a target in antiviral therapy and as some cancers are virus-dependent, RAD52 and SSA may be especially important in such cancers.…”

Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights

“…In some pathways, RAD52 acts as a backup factor (e.g., HR), while in others, it is absolutely required, e.g. single-strand annealing (SSA) at DSBs and break-induced replication (BIR) at single-ended DSBs (which are not shown in this scheme) [8,9,13], (B) RAD52 participates in the alternative lengthening of telomeres. RAD52 plays a role in BIR-mediated elongation of telomeres during pro-metaphase, but also promotes spontaneous telomere elongation in G2, independently of the SLX4 nuclease [11,14,15].…”

“…In the review, "RAD52: viral friend or foe?" Eric Hendrickson evaluates the contribution of RAD52 to viral replication events [13]. Eric Hendrickson made an important contribution to the field when he applied reporter-based DSB repair assays on human RAD52 knockout cells, demonstrating that RAD52 also acts in homology-directed DSB repair pathways other than SSA, as well as that additional RAD52-independent SSA mechanisms must exist in human cells [3].…”

“…In light of the small size of viral genomes, it is clear why hijacking host proteins for DNA recombination and replication is a universal strategy of viruses to integrate, amplify, or protect their genomes from cellular defense mechanisms [44]. In his review, Eric Hendrickson provides an overview of the most diverse roles of RAD52 in the life cycle of different viruses [13]. Thus, the ssDNA virus AAV seems to utilize the host factor RAD52 to reanneal the only necessary cis-acting sequence-the inverted terminal repeat (ITR) secondary structures after unidirectional replication of the viral DNA-priming thereafter the next round of viral replication.…”