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Succinylation at a key residue of FEN1 is involved in the DNA damage response to maintain genome stability
- Source :
- American Journal of Physiology-Cell Physiology. 319:C657-C666
- Publication Year :
- 2020
- Publisher :
- American Physiological Society, 2020.
-
Abstract
- Human flap endonuclease 1 (FEN1) is a structure-specific, multifunctional endonuclease essential for DNA replication and repair. Our previous study showed that in response to DNA damage, FEN1 interacts with the PCNA-like Rad9-Rad1-Hus1 complex instead of PCNA to engage in DNA repair activities, such as stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as ultraviolet (UV) irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintaining genome stability.
- Subjects :
- DNA Replication
Exonucleases
0301 basic medicine
DNA Repair
Flap Endonucleases
Ultraviolet Rays
Physiology
DNA repair
DNA damage
Mitomycin
SUMO-1 Protein
Succinic Acid
Flap structure-specific endonuclease 1
Cell Cycle Proteins
Genomic Instability
03 medical and health sciences
Endonuclease
Succinylation
0302 clinical medicine
Proliferating Cell Nuclear Antigen
Humans
Hydroxyurea
biology
Genome, Human
Chemistry
DNA replication
Sumoylation
Cell Biology
DNA Replication Fork
Cell biology
Proliferating cell nuclear antigen
030104 developmental biology
Multiprotein Complexes
biology.protein
bacteria
Camptothecin
Protein Processing, Post-Translational
030217 neurology & neurosurgery
DNA Damage
Subjects
Details
- ISSN :
- 15221563 and 03636143
- Volume :
- 319
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Cell Physiology
- Accession number :
- edsair.doi.dedup.....369facf4bdd635be7f202afcd40ed93e