 |
PDBsum entry 4x6a
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription/DNA
|
PDB id
|
|
|
|
4x6a
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
1395 a.a.
|
|
|
|
|
|
|
|
|
|
|
1104 a.a.
|
|
|
|
|
|
|
|
|
|
|
266 a.a.
|
|
|
|
|
|
|
|
|
|
|
214 a.a.
|
|
|
|
|
|
|
|
|
|
|
84 a.a.
|
|
|
|
|
|
|
|
|
|
|
133 a.a.
|
|
|
|
|
|
|
|
|
|
|
119 a.a.
|
|
|
|
|
|
|
|
|
|
|
65 a.a.
|
|
|
|
|
|
|
|
|
|
|
114 a.a.
|
|
|
|
|
|
|
|
|
|
|
46 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Mechanism of RNA polymerase ii bypass of oxidative cyclopurine DNA lesions.
|
|
|
Authors
|
|
C.Walmacq,
L.Wang,
J.Chong,
K.Scibelli,
L.Lubkowska,
A.Gnatt,
P.J.Brooks,
D.Wang,
M.Kashlev.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2015,
112,
E410.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
In human cells, the oxidative DNA lesion 8,5'-cyclo-2'-deoxyadenosine (CydA)
induces prolonged stalling of RNA polymerase II (Pol II) followed by
transcriptional bypass, generating both error-free and mutant transcripts with
AMP misincorporated immediately downstream from the lesion. Here, we present
biochemical and crystallographic evidence for the mechanism of CydA recognition.
Pol II stalling results from impaired loading of the template base (5') next to
CydA into the active site, leading to preferential AMP misincorporation. Such
predominant AMP insertion, which also occurs at an abasic site, is unaffected by
the identity of the 5'-templating base, indicating that it derives from
nontemplated synthesis according to an A rule known for DNA polymerases and
recently identified for Pol II bypass of pyrimidine dimers. Subsequent to AMP
misincorporation, Pol II encounters a major translocation block that is slowly
overcome. Thus, the translocation block combined with the poor extension of the
dA.rA mispair reduce transcriptional mutagenesis. Moreover, increasing the
active-site flexibility by mutation in the trigger loop, which increases the
ability of Pol II to accommodate the bulky lesion, and addition of transacting
factor TFIIF facilitate CydA bypass. Thus, blocking lesion entry to the active
site, translesion A rule synthesis, and translocation block are common features
of transcription across different bulky DNA lesions.
|
|
|
|
|
|
|
