Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair
dc.contributor.author | Laverde, Eduardo E. | |
dc.contributor.author | Polyzos, Aris A. | |
dc.contributor.author | Tsegay, Pawlos P. | |
dc.contributor.author | Shaver, Mohammad | |
dc.contributor.author | Hutcheson, Joshua D. | |
dc.contributor.author | Balakrishnan, Lata | |
dc.contributor.author | McMurray, Cynthia T. | |
dc.contributor.author | Liu, Yuan | |
dc.contributor.department | Biology, School of Science | |
dc.date.accessioned | 2023-10-18T17:00:04Z | |
dc.date.available | 2023-10-18T17:00:04Z | |
dc.date.issued | 2022-12-29 | |
dc.description.abstract | Flap 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.version | Final published version | |
dc.identifier.citation | Laverde 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.uri | https://hdl.handle.net/1805/36456 | |
dc.language.iso | en_US | |
dc.publisher | MDPI | |
dc.relation.isversionof | 10.3390/genes14010098 | |
dc.relation.journal | Genes | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.source | PMC | |
dc.subject | R-loop | |
dc.subject | Base excision repair (BER) | |
dc.subject | Flap endonuclease 1 (FEN1) | |
dc.title | Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair | |
dc.type | Article |