Human somatic cells deficient for RAD52 are impaired for viral integration and compromised for most aspects of homology-directed repair

Yinan Kan, Nizar N. Batada, Eric A Hendrickson

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Homology-directed repair (HDR) maintains genomic integrity by eliminating lesions such as DNA double-strand breaks (DSBs), interstrand crosslinks (ICLs) and stalled replication forks and thus a deficiency in HDR is associated with genomic instability and cancer predisposition. The mechanism of HDR is best understood and most rigorously characterized in yeast. The inactivation of the fungal radiation sensitive 52 (RAD52) gene, which has both recombination mediator and single-strand annealing (SSA) activities in vitro, leads to severe HDR defects in vivo. Confusingly, however, the inactivation of murine and chicken RAD52 genes resulted in mouse and chicken cells, respectively, that were largely aphenotypic. To clarify this issue, we have generated RAD52 knockout human cell lines. Human RAD52-null cells retain a significant level of SSA activity demonstrating perforce that additional SSA-like activities must exist in human cells. Moreover, we confirmed that the SSA activity associated with RAD52 is involved in, but not absolutely required for, most HDR subpathways. Specifically, a deficiency in RAD52 impaired the repair of DNA DSBs and intriguingly decreased the random integration of recombinant adeno-associated virus (rAAV). Finally, an analysis of pan-cancer genome data from The Cancer Genome Atlas (TCGA) revealed an association between aberrant levels of RAD52 expression and poor overall survival in multiple cancers. In toto, our work demonstrates that RAD52 contributes to the maintenance of genome stability and tumor suppression in human cells.

Original languageEnglish (US)
Pages (from-to)64-75
Number of pages12
JournalDNA Repair
Volume55
DOIs
StatePublished - Jul 2017

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Keywords

  • DNA double-strand breaks (DSBs)
  • Genome stability
  • Homology-directed repair (HDR)
  • Radiation sensitive 52 (RAD52)
  • Single-strand annealing (SSA)

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