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Poly (ADP-ribose) polymerase 1 is required for protein localization to Cajal body.

Kotova E, Jarnik M, Tulin AV - PLoS Genet. (2009)

Bottom Line: At present, however, while we do know that the main acceptor for pADPr in vivo is PARP1 protein itself, by PARP1 automodification, the significance of PARP1 automodification for in vivo processes is not clear.Specifically, we discovered that PARP1 automodification is required for shuttling key proteins into Cajal body (CB) by protein non-covalent interaction with pADPr in vivo.We hypothesize that PARP1 protein shuttling follows a chain of events whereby, first, most unmodified PARP1 protein molecules bind to chromatin and accumulate in nucleoli, but then, second, upon automodification with poly(ADP-ribose), PARP1 interacts non-covalently with a number of nuclear proteins such that the resulting protein-pADPr complex dissociates from chromatin into CB.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Recently, the nuclear protein known as Poly (ADP-ribose) Polymerase1 (PARP1) was shown to play a key role in regulating transcription of a number of genes and controlling the nuclear sub-organelle nucleolus. PARP1 enzyme is known to catalyze the transfer of ADP-ribose to a variety of nuclear proteins. At present, however, while we do know that the main acceptor for pADPr in vivo is PARP1 protein itself, by PARP1 automodification, the significance of PARP1 automodification for in vivo processes is not clear. Therefore, we investigated the roles of PARP1 auto ADP-ribosylation in dynamic nuclear processes during development. Specifically, we discovered that PARP1 automodification is required for shuttling key proteins into Cajal body (CB) by protein non-covalent interaction with pADPr in vivo. We hypothesize that PARP1 protein shuttling follows a chain of events whereby, first, most unmodified PARP1 protein molecules bind to chromatin and accumulate in nucleoli, but then, second, upon automodification with poly(ADP-ribose), PARP1 interacts non-covalently with a number of nuclear proteins such that the resulting protein-pADPr complex dissociates from chromatin into CB.

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A model of protein delivery to Cajal body by PARP1 shuttling is shown.(1) PARP1 protein is localized in chromatin and nucleoli. (2) Upon activation, PARP1 automodifies and (3) gains the ability to bind by pADPr a number of proteins with pADPr-binding domain. (4) Whole complex consisting of automodified PARP1 and proteins seated on pADPr migrates into Cajal bodies. (5) In CB, complex is disassembled as a result of cleavage of pADPr and released proteins are recycled. PARP1, pADPr protein-complexes of chromatin and nucleolus are indicated. CBm = Cajal body matrix, and Ca = Cajal body cavity.
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pgen-1000387-g007: A model of protein delivery to Cajal body by PARP1 shuttling is shown.(1) PARP1 protein is localized in chromatin and nucleoli. (2) Upon activation, PARP1 automodifies and (3) gains the ability to bind by pADPr a number of proteins with pADPr-binding domain. (4) Whole complex consisting of automodified PARP1 and proteins seated on pADPr migrates into Cajal bodies. (5) In CB, complex is disassembled as a result of cleavage of pADPr and released proteins are recycled. PARP1, pADPr protein-complexes of chromatin and nucleolus are indicated. CBm = Cajal body matrix, and Ca = Cajal body cavity.

Mentions: Most detected in vivo acceptors of pADPr are chromatin proteins (see [2]), but the significance of this modification in vivo is unclear. Since 90–95% of total pADPr is covalently bound to PARP1 itself, the remaining 5–10% of modification by pADPr could be considered as background. Beyond this possibility, however, the dramatic difference between levels of incorporation of ADPr to PARP1 and to other proteins allows us to hypothesize that acceptors of pADPr are not in and of themselves important. Rather, it is the generation of huge, charged shells of pADPr alone that may cause local changes of nuclear architecture and chromatin structure [8],[31],[32]. To explain, large branches of pADPr (i.e., formal negative charge of phosphate groups) may specifically “attract” a number of chromatin proteins and thus cause local temporal removal of those components from chromatin. This specific ability to bind pADPr has been reported for a large list of proteins [33],[34],[35],[36]. In fact, a number of papers report that chromatin changes caused by PARP1 are reversible by degradation of pADPr by PARG [37],[38] and that the same proteins are then re-utilized for chromatin reassembly. These observations finally led to the model of “histone shuttling” during PARP-induced chromatin changes [31],[32],[39]. However, since the present study reports the accumulation of automodified PARP1 protein, proteins modified by PARP1 and proteins interacting with pADPr in Cajal bodies (CBs), we propose a model whereby automodified PARP1 may directly deliver components of chromatin and nucleolus to CBs in a way that permits their release by PARG, thus allowing their reassembly into active protein complexes (Figure 7).


Poly (ADP-ribose) polymerase 1 is required for protein localization to Cajal body.

Kotova E, Jarnik M, Tulin AV - PLoS Genet. (2009)

A model of protein delivery to Cajal body by PARP1 shuttling is shown.(1) PARP1 protein is localized in chromatin and nucleoli. (2) Upon activation, PARP1 automodifies and (3) gains the ability to bind by pADPr a number of proteins with pADPr-binding domain. (4) Whole complex consisting of automodified PARP1 and proteins seated on pADPr migrates into Cajal bodies. (5) In CB, complex is disassembled as a result of cleavage of pADPr and released proteins are recycled. PARP1, pADPr protein-complexes of chromatin and nucleolus are indicated. CBm = Cajal body matrix, and Ca = Cajal body cavity.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2637609&req=5

pgen-1000387-g007: A model of protein delivery to Cajal body by PARP1 shuttling is shown.(1) PARP1 protein is localized in chromatin and nucleoli. (2) Upon activation, PARP1 automodifies and (3) gains the ability to bind by pADPr a number of proteins with pADPr-binding domain. (4) Whole complex consisting of automodified PARP1 and proteins seated on pADPr migrates into Cajal bodies. (5) In CB, complex is disassembled as a result of cleavage of pADPr and released proteins are recycled. PARP1, pADPr protein-complexes of chromatin and nucleolus are indicated. CBm = Cajal body matrix, and Ca = Cajal body cavity.
Mentions: Most detected in vivo acceptors of pADPr are chromatin proteins (see [2]), but the significance of this modification in vivo is unclear. Since 90–95% of total pADPr is covalently bound to PARP1 itself, the remaining 5–10% of modification by pADPr could be considered as background. Beyond this possibility, however, the dramatic difference between levels of incorporation of ADPr to PARP1 and to other proteins allows us to hypothesize that acceptors of pADPr are not in and of themselves important. Rather, it is the generation of huge, charged shells of pADPr alone that may cause local changes of nuclear architecture and chromatin structure [8],[31],[32]. To explain, large branches of pADPr (i.e., formal negative charge of phosphate groups) may specifically “attract” a number of chromatin proteins and thus cause local temporal removal of those components from chromatin. This specific ability to bind pADPr has been reported for a large list of proteins [33],[34],[35],[36]. In fact, a number of papers report that chromatin changes caused by PARP1 are reversible by degradation of pADPr by PARG [37],[38] and that the same proteins are then re-utilized for chromatin reassembly. These observations finally led to the model of “histone shuttling” during PARP-induced chromatin changes [31],[32],[39]. However, since the present study reports the accumulation of automodified PARP1 protein, proteins modified by PARP1 and proteins interacting with pADPr in Cajal bodies (CBs), we propose a model whereby automodified PARP1 may directly deliver components of chromatin and nucleolus to CBs in a way that permits their release by PARG, thus allowing their reassembly into active protein complexes (Figure 7).

Bottom Line: At present, however, while we do know that the main acceptor for pADPr in vivo is PARP1 protein itself, by PARP1 automodification, the significance of PARP1 automodification for in vivo processes is not clear.Specifically, we discovered that PARP1 automodification is required for shuttling key proteins into Cajal body (CB) by protein non-covalent interaction with pADPr in vivo.We hypothesize that PARP1 protein shuttling follows a chain of events whereby, first, most unmodified PARP1 protein molecules bind to chromatin and accumulate in nucleoli, but then, second, upon automodification with poly(ADP-ribose), PARP1 interacts non-covalently with a number of nuclear proteins such that the resulting protein-pADPr complex dissociates from chromatin into CB.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Recently, the nuclear protein known as Poly (ADP-ribose) Polymerase1 (PARP1) was shown to play a key role in regulating transcription of a number of genes and controlling the nuclear sub-organelle nucleolus. PARP1 enzyme is known to catalyze the transfer of ADP-ribose to a variety of nuclear proteins. At present, however, while we do know that the main acceptor for pADPr in vivo is PARP1 protein itself, by PARP1 automodification, the significance of PARP1 automodification for in vivo processes is not clear. Therefore, we investigated the roles of PARP1 auto ADP-ribosylation in dynamic nuclear processes during development. Specifically, we discovered that PARP1 automodification is required for shuttling key proteins into Cajal body (CB) by protein non-covalent interaction with pADPr in vivo. We hypothesize that PARP1 protein shuttling follows a chain of events whereby, first, most unmodified PARP1 protein molecules bind to chromatin and accumulate in nucleoli, but then, second, upon automodification with poly(ADP-ribose), PARP1 interacts non-covalently with a number of nuclear proteins such that the resulting protein-pADPr complex dissociates from chromatin into CB.

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