PGBD5 binds to PSS sequences to promote somatic genomic rearrangements in rhabdoid tumor cells.
Major finding: PGBD5 binds to PSS sequences to promote somatic genomic rearrangements in rhabdoid tumor cells.
Clinical relevance: Rhabdoid tumors harbor previously unrecognized rearrangements with PSS sequences at the breakpoints.
Impact: PGBD5 activity may induce the site-specific DNA rearrangements found in pediatric and adult tumors.
Many pediatric cancers harbor complex genomic rearrangements in the absence of widespread genomic instability. It has been hypothesized that DNA recombinases may lead to somatic DNA rearrangements in these tumors, but the responsible recombinases have not been identified. Hennsen, Koche, and colleagues found that PGBD5, a recently discovered transposase-derived gene, is highly expressed in a variety of solid tumors including rhabdoid tumors. In human rhabdoid tumors, SMARCB1, which is frequently subject to inactivating mutations, was found to be involved in previously unrecognized recurrent somatic deletions, inversions, and translocations marked by PGBD5-specific signal (PSS) sequences at their breakpoints. Further, recurrent PSS sequence–associated rearrangements occurred in CNTNAP2, TENM2, TENM3, and TET2. Overall, 580 of the 1,121 somatic genomic rearrangements detected in 31 rhabdoid tumors had PSS sequences near the breakpoints. PGBD5 bound directly to PSS sequences and was sufficient to induce DNA rearrangements in rhabdoid tumor cells by mediating integration of transposon-containing DNA into PSS-containing sites. Expression of PGBD5 was sufficient to transform genomically stable primary cells both in vitro and in vivo, and required the enzymatic nuclease activity of PGBD5 and DNA repair by nonhomologous end-joining (NHEJ). Moreover, transient PGBD5 expression was sufficient for transformation, consistent with transposase-induced heritable alterations. Sequencing of PGBD5-induced tumors revealed site-specific rearrangements associated with PSS sequences. Collectively, these findings identify PGBD5 as an endogenous human DNA transposase sufficient to induce site-specific genomic rearrangements to transform cells in the absence of chromosomal instability and suggest a mechanism by which site-specific DNA rearrangements may occur in solid tumors. Further, these results suggest the possibility of targeting NHEJ or transposase activity in PGBD5-driven tumors.
Henssen AG, Koche R, Zhuang J, Jiang E, Reed C, Eisenberg A, et al. PGBD5 promotes site-specific oncogenic mutations in human tumors. Nat Genet 2017 May 15 [Epub ahead of print].
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