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Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A.

Andersen PL, Zhou H, Pastushok L, Moraes T, McKenna S, Ziola B, Ellison MJ, Dixit VM, Xiao W - J. Cell Biol. (2005)

Bottom Line: In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2.Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains.Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.

ABSTRACT
Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13-Mms2 is required for DNA damage repair but not nuclear factor kappaB (NF-kappaB) activation, whereas Ubc13-Uev1A is involved in NF-kappaB activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

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Related in: MedlinePlus

A working model of Ubc13–Uev functions in human cells. This model is based on data and discussion presented in this paper as well as some previous papers. Please note that a mammalian Rad5 homologue has not been identified.
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fig9: A working model of Ubc13–Uev functions in human cells. This model is based on data and discussion presented in this paper as well as some previous papers. Please note that a mammalian Rad5 homologue has not been identified.

Mentions: In summary, we demonstrate that Ubc13-mediated ubiquitination can coordinate cellular responses to both DNA damage as well as nongenotoxic stresses; its target selection and mode of response (e.g., DNA repair or cell proliferation) is determined not only by E3 proteins but also by a Uev as its regulatory subunit. Hence, we propose that the Uevs serve as an essential modulator of E2 ubiquitination activity. A working model based on the aforementioned analyses is depicted in Fig. 9. It should be noted that the aforementioned possibilities are not mutually exclusive. For example, Uev1A can recruit Ubc13 to a process that directly promotes tumorigenesis and meanwhile prevent Ubc13–Mms2-mediated error-free DNA repair.


Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A.

Andersen PL, Zhou H, Pastushok L, Moraes T, McKenna S, Ziola B, Ellison MJ, Dixit VM, Xiao W - J. Cell Biol. (2005)

A working model of Ubc13–Uev functions in human cells. This model is based on data and discussion presented in this paper as well as some previous papers. Please note that a mammalian Rad5 homologue has not been identified.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171356&req=5

fig9: A working model of Ubc13–Uev functions in human cells. This model is based on data and discussion presented in this paper as well as some previous papers. Please note that a mammalian Rad5 homologue has not been identified.
Mentions: In summary, we demonstrate that Ubc13-mediated ubiquitination can coordinate cellular responses to both DNA damage as well as nongenotoxic stresses; its target selection and mode of response (e.g., DNA repair or cell proliferation) is determined not only by E3 proteins but also by a Uev as its regulatory subunit. Hence, we propose that the Uevs serve as an essential modulator of E2 ubiquitination activity. A working model based on the aforementioned analyses is depicted in Fig. 9. It should be noted that the aforementioned possibilities are not mutually exclusive. For example, Uev1A can recruit Ubc13 to a process that directly promotes tumorigenesis and meanwhile prevent Ubc13–Mms2-mediated error-free DNA repair.

Bottom Line: In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2.Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains.Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.

ABSTRACT
Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13-Mms2 is required for DNA damage repair but not nuclear factor kappaB (NF-kappaB) activation, whereas Ubc13-Uev1A is involved in NF-kappaB activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

Show MeSH
Related in: MedlinePlus