Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragment...Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.展开更多
RAD9 regulates multiple cellular processes that influence genomic integrity,and for at least some of its functions the protein acts as part of a heterotrimeric complex bound to HUS1 and RAD1 proteins.RAD9 participates...RAD9 regulates multiple cellular processes that influence genomic integrity,and for at least some of its functions the protein acts as part of a heterotrimeric complex bound to HUS1 and RAD1 proteins.RAD9 participates in DNA repair,including base excision repair,homologous recombination repair and mismatch repair,multiple cell cycle phase checkpoints and apoptosis.In addition,functions including the transactivation of downstream target genes,immunoglobulin class switch recombination,as well as 3′–5′exonuclease activity have been reported.Aberrant RAD9 expression has been linked to breast,lung,thyroid,skin and prostate tumorigenesis,and a cause–effect relationship has been demonstrated for the latter two.Interestingly,human RAD9 overproduction correlates with prostate cancer whereas deletion of Mrad9,the corresponding mouse gene,in keratinocytes leads to skin cancer.These results reveal that RAD9 protein can function as an oncogene or tumor suppressor,and aberrantly high or low levels can have deleterious health consequences.It is not clear which of the many functions of RAD9 is critical for carcinogenesis,but several alternatives are considered herein and implications for the development of novel cancer therapies based on these findings are examined.展开更多
基金This work was supported by grants from the National Basic Research Program of China （2015CB910600）, the National Natural Science Foundation of China （31700688）, the National Key Research and Development Program of China （2017YFA0503900）, and the Natural Science Foundation of Zhejiang Province （LY16C050003） to Y.I.H. and H.X. A part of the work presented in the current article was supported by the National Institutes of Health grants ROICA073764 to B.H.S and R50CA211397 to L.Z.
文摘Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.
基金supported by National Institutes of Health grants CA130536,CA049062,ES017557 and GM079107.
文摘RAD9 regulates multiple cellular processes that influence genomic integrity,and for at least some of its functions the protein acts as part of a heterotrimeric complex bound to HUS1 and RAD1 proteins.RAD9 participates in DNA repair,including base excision repair,homologous recombination repair and mismatch repair,multiple cell cycle phase checkpoints and apoptosis.In addition,functions including the transactivation of downstream target genes,immunoglobulin class switch recombination,as well as 3′–5′exonuclease activity have been reported.Aberrant RAD9 expression has been linked to breast,lung,thyroid,skin and prostate tumorigenesis,and a cause–effect relationship has been demonstrated for the latter two.Interestingly,human RAD9 overproduction correlates with prostate cancer whereas deletion of Mrad9,the corresponding mouse gene,in keratinocytes leads to skin cancer.These results reveal that RAD9 protein can function as an oncogene or tumor suppressor,and aberrantly high or low levels can have deleterious health consequences.It is not clear which of the many functions of RAD9 is critical for carcinogenesis,but several alternatives are considered herein and implications for the development of novel cancer therapies based on these findings are examined.
基金supported by grants from The National Natural Science Foundation of China(Y4JM061001,Y5JY011001,81072093)The Natural Science Foundation of Hebei Province(C2012401039)~~
