Base Flipping

Roberts, Richard J.; Cheng, Xiaodong

doi:10.1146/annurev.biochem.67.1.181

Cited by 320 publications

(267 citation statements)

References 58 publications

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“…The idea that MutS proteins may flip mismatched bases has been proposed earlier based on several lines of evidence [2,44]. It is well known that several other DNA repair enzymes excise damaged DNA bases only after flipping them out of the helix [45][46][47][48]. Replacing Glu339 with an alanine could impair flipping of bases in mismatches that have nearly normal geometry and/or high stability, e.g., 8-oxoGsyn•A mismatches.…”

Section: The Function Of Glu339 In Yeast Msh6mentioning

confidence: 99%

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

et al. 2007

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The major eukaryotic mismatch repair (MMR) pathway requires Msh2-Msh6, which, like E. coli MutS, binds to and participates in repair of the two most common replication errors, single base-base and single base insertion-deletion mismatches. For both types of mismatches, the side chain of E. coli Glu38 in a conserved Phe-X-Glu motif interacts with a mismatched base. The Oε of Glu38 forms a hydrogen bond with either the N7 of purines or the N3 of pyrimidines. We show here that changing E. coli Glu38 to alanine results in nearly complete loss of repair of both single base-base and single base deletion mismatches. In contrast, a yeast strain with alanine replacing homologous Glu339 in Msh6 has nearly normal repair for insertion-deletion and most base-base mismatches, but is defective in repairing base-base mismatches characteristic of oxidative stress, e.g., 8-oxo-G•A mismatches. The results suggest that bacterial MutS and yeast Msh2-Msh6 differ in how they recognize and/or process replication errors involving undamaged bases, and that Glu339 in Msh6 may have a specialized role in repairing mismatches containing oxidized bases.

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Section: The Function Of Glu339 In Yeast Msh6mentioning

confidence: 99%

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

et al. 2007

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“…This would allow the use of a fairly simple mechanism, e.g., some form of base flipping (23), to generate the ϳ18 bp of melting that we observe in the left flank of the wt template.…”

Section: Vol 81 2007mentioning

confidence: 99%

ATP-Dependent Minor Groove Recognition of TA Base Pairs Is Required for Template Melting by the E1 Initiator Protein

Schuck

Stenlund

2007

J Virol

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Template melting is an essential step in the initiation of DNA replication, but the mechanism of template melting is unknown for any replicon. Here we demonstrate that melting of the bovine papillomavirus type 1 ori is a sequence-dependent process which relies on specific recognition of TA base pairs in the minor groove by the E1 initiator. We show that correct template melting is a prerequisite for the formation of a stable double hexamer with helicase activity and that ori mutants that fail to melt correctly are defective for ori unwinding and DNA replication in vivo. Our results also indicate that melting of the DNA is achieved by destabilization of the double helix along its length through multiple interactions with E1, each of which is responsible for melting of a few base pairs, resulting in the extensive melting that is required for initiation of DNA replication.Template melting is an essential step in the initiation of replication of double-stranded DNA. In spite of its fundamental importance for DNA replication, the melting process is almost entirely uncharacterized. For Escherichia coli, the initiator DnaA has long been known to melt OriC, as can be detected by the use of single-stranded DNA (ssDNA)-specific nucleases (6, 32). The mechanism by which the DNA is melted is unknown, but it is established that melting is dependent on nucleotide binding by DnaA (for a review, see reference 16). For eukaryotes, although the origin recognition complex has been identified as the factor that marks the replicator (2), an activity that can melt the DNA in preparation for replication has still not been identified. Viral initiator proteins such as the simian virus 40 (SV40) large T antigen (T-Ag) and the papillomavirus E1 protein have long been known to melt their respective origins of DNA replication, as detected by oxidation with KMnO 4 (4,5,14,22,24,25). However, little information exists about which forms of these proteins execute melting, which parts of the polypeptide are responsible for the melting activity, and whether this process is DNA sequence dependent (5, 27).The E1 proteins from papillomaviruses are ϳ70-kDa polypeptides which, in addition to DNA melting activity, have DNA helicase activity (19,20,30,33,35,37,38,40) and also bind DNA. DNA binding by E1 is the result of two different DNA binding activities. Site-specific DNA binding is provided by the E1 DNA binding domain (DBD), which recognizes and binds to two pairs of E1 binding sites (E1 BS) in the origin of replication (7-9, 11, 15, 17, 31, 36). The E1 helicase domain binds DNA with low sequence specificity, and this activity is required for the ability of the E1 helicase domain to contact the DNA sequences flanking the E1 BS, including a region that has been termed the A/T-rich region (34).Recent advances in the study of E1 and T-Ag have opened up the melting process for more detailed study. Structural studies of E1 and T-Ag have provided important information about the domain structure, how these proteins oligomerize, and how they bind and hydro...

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“…1). Like in all other structures of DNA MTases with substrate DNA [4][5][6][7] and initially discovered with M.HhaI [8], the target Cyt is rotated out of the DNA helix and bound to a pocket in the protein, which presents the active site residues conserved among DNA-(cytosine C5)-methyltransferases [4,7]. Unexpectedly, in the Dnmt1-DNA structure the orphan Gua residue from the non-target strand forms a base pair with a Gua from a Gua:Cyt base pair 5 0 of the CpG site.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic details of the DNA recognition by the Dnmt1 DNA methyltransferase

2012

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a b s t r a c tA recently solved Dnmt1-DNA crystal structure revealed several enzyme-DNA contacts and large structural rearrangements of the DNA at the target site, including the flipping of the non-target strand base of the base pair flanking the CpG site and formation of a non-canonical base pair between the non-target strand Gua and the flanking base pair. Here, we show that the contacts of the enzyme to the target base and the Gua:5mC base pair that are observed in the structure are very important for catalytic activity. The contacts to the non-target strand Gua are not important since its exchange by Ade stimulated activity. Except target base flipping, we could not find evidence that the DNA rearrangements have a functional role.

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Base Flipping

Cited by 320 publications

References 58 publications

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

ATP-Dependent Minor Groove Recognition of TA Base Pairs Is Required for Template Melting by the E1 Initiator Protein

Mechanistic details of the DNA recognition by the Dnmt1 DNA methyltransferase

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