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PDBsum entry 2zvm
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References listed in PDB file
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Key reference
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Title
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Structural basis for novel interactions between human translesion synthesis polymerases and proliferating cell nuclear antigen.
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Authors
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A.Hishiki,
H.Hashimoto,
T.Hanafusa,
K.Kamei,
E.Ohashi,
T.Shimizu,
H.Ohmori,
M.Sato.
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Ref.
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J Biol Chem, 2009,
284,
10552-10560.
[DOI no: ]
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PubMed id
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Abstract
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Translesion synthesis (TLS) is a DNA damage tolerance mechanism that allows
continued DNA synthesis, even in the presence of damaged DNA templates. Mammals
have multiple DNA polymerases specialized for TLS, including Poleta, Poliota,
and Polkappa. These enzymes show preferential bypass for different lesions.
Proliferating cell nuclear antigen (PCNA), which functions as a sliding clamp
for the replicative polymerase Poldelta, also interacts with the three TLS
polymerases. Although many PCNA-binding proteins have a highly conserved
sequence termed the PCNA-interacting protein box (PIP-box), Poleta, Poliota, and
Polkappa have a noncanonical PIP-box sequence. In response to DNA damage,
Lys-164 of PCNA undergoes ubiquitination by the RAD6-RAD18 complex, and the
ubiquitination is considered to facilitate TLS. Consistent with this, these
three TLS polymerases have one or two ubiquitin binding domains and are
recruited to replication forks via interactions with ubiquitinated PCNA
involving the noncanonical PIP-box and ubiquitin binding domain. However, it is
unclear how these TLS polymerases interact with PCNA. To address the structural
basis for interactions between different TLS polymerases and PCNA, we determined
crystal structures of PCNA bound to peptides containing the noncanonical PIP-box
of these polymerases. We show that the three PIP-box peptides interact with PCNA
in different ways, both from one another and from canonical PIP-box peptides.
Especially, the PIP-box of Poliota adopts a novel structure. Furthermore, these
structures enable us to speculate how these TLS polymerases interact with
Lys-164-monoubiquitinated PCNA. Our results will provide clues to understanding
the mechanism of preferential recruitment of TLS polymerases to the stalled
forks.
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Figure 3.
Hydrophobic plug-socket interaction of the Polη (A) or Polι
(B) peptide with PCNA and superimposition of PIP-box structures
bound to PCNA (C). A and B, PCNA is shown by a surface model,
and residues of PCNA that interact with the three-forked
hydrophobic plug are colored gray. PIP-box residues are shown by
stick models. Residues of PCNA that interact with the Met-701
(p1) residue of Polη in the Q-pocket are colored light pink. C,
structures of p21, Polη, Polκ, and Polι bound to PCNA are
shown in light blue, pink, green, and yellow, respectively.
PIP-box residues are shown by stick models, and only some
PIP-box residues of Polι are denoted.
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Figure 5.
Proposed models of the interaction of
Lys-164-monoubiquitinated PCNA with Polη or Polκ (A) and Polι
(B). The ubiquitin moieties linked to Lys-164 are shown by
ellipsoids. N- and C-terminal sides of TLS polymerase fragments
are indicated by N and C, respectively.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
10552-10560)
copyright 2009.
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