Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair

dc.contributor.authorLaverde, Eduardo E.
dc.contributor.authorPolyzos, Aris A.
dc.contributor.authorTsegay, Pawlos P.
dc.contributor.authorShaver, Mohammad
dc.contributor.authorHutcheson, Joshua D.
dc.contributor.authorBalakrishnan, Lata
dc.contributor.authorMcMurray, Cynthia T.
dc.contributor.authorLiu, Yuan
dc.contributor.departmentBiology, School of Science
dc.date.accessioned2023-10-18T17:00:04Z
dc.date.available2023-10-18T17:00:04Z
dc.date.issued2022-12-29
dc.description.abstractFlap endonuclease 1 (FEN1) is an essential enzyme that removes RNA primers and base lesions during DNA lagging strand maturation and long-patch base excision repair (BER). It plays a crucial role in maintaining genome stability and integrity. FEN1 is also implicated in RNA processing and biogenesis. A recent study from our group has shown that FEN1 is involved in trinucleotide repeat deletion by processing the RNA strand in R-loops through BER, further suggesting that the enzyme can modulate genome stability by facilitating the resolution of R-loops. However, it remains unknown how FEN1 can process RNA to resolve an R-loop. In this study, we examined the FEN1 cleavage activity on the RNA:DNA hybrid intermediates generated during DNA lagging strand processing and BER in R-loops. We found that both human and yeast FEN1 efficiently cleaved an RNA flap in the intermediates using its endonuclease activity. We further demonstrated that FEN1 was recruited to R-loops in normal human fibroblasts and senataxin-deficient (AOA2) fibroblasts, and its R-loop recruitment was significantly increased by oxidative DNA damage. We showed that FEN1 specifically employed its endonucleolytic cleavage activity to remove the RNA strand in an R-loop during BER. We found that FEN1 coordinated its DNA and RNA endonucleolytic cleavage activity with the 3'-5' exonuclease of APE1 to resolve the R-loop. Our results further suggest that FEN1 employed its unique tracking mechanism to endonucleolytically cleave the RNA strand in an R-loop by coordinating with other BER enzymes and cofactors during BER. Our study provides the first evidence that FEN1 endonucleolytic cleavage can result in the resolution of R-loops via the BER pathway, thereby maintaining genome integrity.
dc.eprint.versionFinal published version
dc.identifier.citationLaverde EE, Polyzos AA, Tsegay PP, et al. Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair. Genes (Basel). 2022;14(1):98. Published 2022 Dec 29. doi:10.3390/genes14010098
dc.identifier.urihttps://hdl.handle.net/1805/36456
dc.language.isoen_US
dc.publisherMDPI
dc.relation.isversionof10.3390/genes14010098
dc.relation.journalGenes
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.sourcePMC
dc.subjectR-loop
dc.subjectBase excision repair (BER)
dc.subjectFlap endonuclease 1 (FEN1)
dc.titleFlap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair
dc.typeArticle
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