Replication across Template T/U by Human DNA Polymerase-ι

Jain, Rinku; Nair, D.T.; Johnson, Robert E.; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

doi:10.1016/j.str.2009.04.011

Cited by 20 publications

(33 citation statements)

References 32 publications

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“…The lack of any involvement of Pol in CPD bypass is in keeping with the biochemical studies indicating that this Pol is strongly inhibited in synthesizing DNA opposite a cis-syn TT dimer (18,19). Also, structural studies have indicated that the two covalently linked pyrimidine residues of a CPD could not be accommodated in the Pol active site (20)(21)(22). And moreover, even opposite undamaged T and C residues, Pol inserts nucleotides with a very low efficiency and fidelity (18,19).…”

Section: Pol Has No Role In Tls Oppositesupporting

confidence: 63%

Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells

Yoon

Prakash

2009

Proc. Natl. Acad. Sci. U.S.A.

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137

205

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Cyclobutane pyrimidine dimers (CPDs) constitute the most frequent UV-induced DNA photoproduct. However, it has remained unclear how human and other mammalian cells mitigate the mutagenic and carcinogenic potential of CPDs emanating from their replicative bypass. Here, we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in the replicative bypass of a cis-syn TT dimer carried on the leading or the lagging strand DNA template in a plasmid system we have designed, and we determine in mouse cells the frequencies and mutational spectra generated from TLS occurring specifically opposite CPDs formed at TT, TC, and CC dipyrimidine sites. From these studies we draw the following conclusions: (i) TLS makes a very prominent contribution to CPD bypass on both the DNA strands during replication; (ii) Pols , , and provide alternate pathways for TLS opposite CPDs wherein Pols and promote mutagenic TLS opposite CPDs; and (iii) the absence of mutagenic TLS events opposite a cis-syn TT dimer in human cells and opposite CPDs formed at TT, TC, and CC sites in mouse cells that we observe upon the simultaneous knockdown of Pols and implicates a highly error-free role of Pol in TLS opposite CPDs in mammalian cells. Such a remarkably high in vivo fidelity of Pol could not have been anticipated in view of its low intrinsic fidelity. These observations have important bearing on how mammalian cells have adapted to avoid the mutagenic and carcinogenic consequences of exposure to sunlight.DNA damage and repair ͉ translesion synthesis ͉ UV damage U V light induces the formation of two major photoproducts, cis-syn cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4) PPs]. Of the two lesions, (6-4) PPs are removed rapidly and efficiently by nucleotide excision repair (NER), whereas the removal of CPDs by NER occurs at a much slower rate (1); hence, CPDs constitute a much more important premutagenic lesion than (6-4) PPs, and it has been estimated that CPDs account for Ϸ80% of UV-induced mutations in mammalian cells (2). Because of their relatively high abundance, slow repair, and the fact that CPDs account for a large majority of UV-induced mutations (3, 4), in this study we determine the roles that human and mouse translesion synthesis (TLS) Pols , , , and play in TLS opposite CPDs and the relative contributions they make to their error-free vs. mutagenic bypass.For TLS studies in human cells, we have designed a duplex plasmid system in which bidirectional replication ensues from a replication origin and proceeds through a site-specific cis-syn TT dimer carried on the leading or the lagging DNA strand template. Studies with this plasmid system in human cells have allowed us to make several unanticipated observations, some of which we note here: (i) opposite a cis-syn TT dimer, TLS makes an important contribution to lesion bypass and is predominantly error-free; (ii) different TLS Pols contribute similarly to lesion bypass on the leading and lagging DNA strands; (iii) Po...

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Section: Pol Has No Role In Tls Oppositesupporting

confidence: 63%

Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells

Yoon

Prakash

2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

205

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“…The binding site S 1 is composed of residues located in the fingers subdomain (see Figure 3a or 4a). However, in contrast to the replicative Pol where the binding site S 1 has a high affinity for the unpaired bases and/or the sugar-phosphate backbone of the ssDNA template, the binding site S 1 in the Y-family Pol has a very low or even no affinity, which is consistent with the available structural studies [27,28,32,41,42]. The binding site S 2 , which is composed of residues located in the thumb domain and mainly in the LF domain (see Figure 3a or 4a), has a high affinity for dsDNA, which is also consistent with the available structural studies [27,28,32,41,42].…”

Section: Methodssupporting

confidence: 85%

A nucleotide binding rectification Brownian ratchet model for translocation of Y-family DNA polymerases

Xie

2011

Theor Biol Med Model

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Y-family DNA polymerases are characterized by low-fidelity synthesis on undamaged DNA and ability to catalyze translesion synthesis over the damaged DNA. Their translocation along the DNA template is an important event during processive DNA synthesis. In this work we present a Brownian ratchet model for this translocation, where the directed translocation is rectified by the nucleotide binding to the polymerase. Using the model, different features of the available structures for Dpo4, Dbh and polymerase ι in binary and ternary forms can be easily explained. Other dynamic properties of the Y-family polymerases such as the fast translocation event upon dNTP binding for Dpo4 and the considerable variations of the processivity among the polymerases can also be well explained by using the model. In addition, some predicted results of the DNA synthesis rate versus the external force acting on Dpo4 and Dbh polymerases are presented. Moreover, we compare the effect of the external force on the DNA synthesis rate of the Y-family polymerase with that of the replicative DNA polymerase.

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“…The structure of pol ι in a ternary complex with a template dT and incoming dATP was modeled on the BrU/dGTP (PDB code 3H4D) published structures (34). The BrU is replaced by a normal thymine, and the dGTP is replaced by dATP.…”

Section: Methodsmentioning

confidence: 99%

The Steric Gate of DNA Polymerase ι Regulates Ribonucleotide Incorporation and Deoxyribonucleotide Fidelity

Donigan

McLenigan

Yang

et al. 2014

Journal of Biological Chemistry

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Background: Accurate bypass of DNA damage by translesion DNA polymerases is critical for cell survival.Results: Wild-type human DNA polymerase ι incorporates ribonucleotides, and a steric gate mutant increases both ribonucleotide incorporation and deoxyribonucleotide selectivity.Conclusion: A single amino acid residue in DNA polymerase ι limits incorporation of ribonucleotides into DNA.Significance: DNA polymerase ι may incorporate ribonucleotides during translesion DNA synthesis.

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Replication across Template T/U by Human DNA Polymerase-ι

Cited by 20 publications

References 32 publications

Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells

Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells

A nucleotide binding rectification Brownian ratchet model for translocation of Y-family DNA polymerases

The Steric Gate of DNA Polymerase ι Regulates Ribonucleotide Incorporation and Deoxyribonucleotide Fidelity

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