Structural diversity of the Y-family DNA polymerases

Pata, Janice D.

doi:10.1016/j.bbapap.2010.01.020

Cited by 82 publications

(88 citation statements)

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“…In contrast, the failure to promote 21 events at homo-pyrimidine tracts, which we documented in two distinct experimental contexts (normal growth and OMT), is not consistent with the strong deletogenic propensity of Dbh demonstrated repeatedly in vitro (Potapova et al 2002;Wilson and Pata 2008). The formal possibility remains that deletogenesis on intact template reflects some artifact of in vitro assays, but this seems unlikely, as this property has been linked to specific structural features of the polymerase Pata 2010) and conformational dynamics of the template in the enzyme active site (Wilson and Pata 2008;Manjari et al 2014). Conversely, deletogenesis seems unlikely to be masked in vivo by nonspecific factors, such as cytoplasmic solutes or elevated temperature.…”

Section: Discussioncontrasting

confidence: 46%

“…Large catalytic sites, combined with the absence of proofreading activity, allow these polymerases to insert nucleotides opposite diverse DNA lesions, but also limit the accuracy with which they replicate intact template (Yang and Woodgate 2007;Pata 2010). This latter property creates a risk of mutagenesis, which is mitigated somewhat by other features of these enzymes, including low processivity and a bias toward insertion of the correct nucleotide opposite certain DNA lesions (Jarosz et al 2007 are nevertheless subject to mechanisms that limit their access to template and coordinate TLS with other lesion-bypass strategies.…”

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confidence: 99%

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Lesion-Induced Mutation in the Hyperthermophilic Archaeon Sulfolobus acidocaldarius and Its Avoidance by the Y-Family DNA Polymerase Dbh

Sakofsky

Grogan

2015

Genetics

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Hyperthermophilic archaea offer certain advantages as models of genome replication, and Sulfolobus Y-family polymerases Dpo4 (S. solfataricus) and Dbh (S. acidocaldarius) have been studied intensively in vitro as biochemical and structural models of trans-lesion DNA synthesis (TLS). However, the genetic functions of these enzymes have not been determined in the native context of living cells. We developed the first quantitative genetic assays of replication past defined DNA lesions and error-prone motifs in Sulfolobus chromosomes and used them to measure the efficiency and accuracy of bypass in normal and dbh 2 strains of Sulfolobus acidocaldarius. Oligonucleotide-mediated transformation allowed low levels of abasic-site bypass to be observed in S. acidocaldarius and demonstrated that the local sequence context affected bypass specificity; in addition, most erroneous TLS did not require Dbh function. Applying the technique to another common lesion, 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), revealed an antimutagenic role of Dbh. The efficiency and accuracy of replication past 8-oxo-dG was higher in the presence of Dbh, and up to 90% of the Dbh-dependent events inserted dC. A third set of assays, based on phenotypic reversion, showed no effect of Dbh function on spontaneous 21 frameshifts in mononucleotide tracts in vivo, despite the extremely frequent slippage at these motifs documented in vitro. Taken together, the results indicate that a primary genetic role of Dbh is to avoid mutations at 8-oxo-dG that occur when other Sulfolobus enzymes replicate past this lesion. The genetic evidence that Dbh is recruited to 8-oxo-dG raises questions regarding the mechanism of recruitment, since Sulfolobus spp. have eukaryotic-like replisomes but no ubiquitin.KEYWORDS trans-lesion DNA synthesis (TLS); abasic site; 7,8-dihydro-8-oxo-deoxyguanosine; oligonucleotide-mediated transformation T HE fact that DNA damage occurs in all living cells poses a threat to the accurate replication and partitioning of their genomes. Cells counter this threat with an array of diverse damage-coping systems, some of which repair the DNA, whereas others enable replication to continue past persistent lesions. Lesion bypass, also termed "damage tolerance," can follow various alternatives, which are broadly distinguished as error-free vs. error-prone (Lehmann et al. 2007). The error-free pathways generally use recombinationassociated functions to pair a strand, newly synthesized on intact template, to the damaged DNA strand; the mechanisms for this include transient reversal of the replication fork and strand exchange at gaps left behind the fork (Sale 2012). These mechanisms bypass lesions accurately, although they can promote other forms of genetic instability, such as ectopic recombination between dispersed repeats (Izhar et al. 2013).Error-prone mechanisms of lesion bypass, in contrast, use specialized, trans-lesion synthesis (TLS) polymerases to continue strand elongation using the damaged template; most of these enzymes belong to t...

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Section: Discussioncontrasting

confidence: 46%

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confidence: 99%

Lesion-Induced Mutation in the Hyperthermophilic Archaeon Sulfolobus acidocaldarius and Its Avoidance by the Y-Family DNA Polymerase Dbh

Sakofsky

Grogan

2015

Genetics

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“…Members of the Y-family share canonical polymerase architecture consisting of a catalytic core composed of palm, fingers, and thumb domains, and have an additional unique C-terminal domain termed the ''wrist'', ''polymerase-associated domain'' (PAD), or ''little finger'' (LF) domain. Notably, the LF domain is tethered to the catalytic core by a flexible linker and has been found to occupy a variety of conformations (Pata 2010). Y-family polymerases also have a significantly larger active site than that of replicative polymerases, which allows the accommodation of bulky DNA adducts, but increases the error-rate extending primers across from undamaged DNA (Sale et al 2012).…”

Section: Biological Contextmentioning

confidence: 99%

1H, 13C, and 15N backbone resonance assignments of the full-length 40 kDa S. acidocaldarius Y-family DNA polymerase, dinB homolog

Moro

Cocco

2015

Biomol NMR Assign

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“…Similar interactions are also present in another member of the family, human DNA polymerase iota (1ZET) (47) (reviewed in ref. 48). (E) A member of the B-family DNA polymerase, Enterobacteria phage RB69 DNA polymerase (3NCI) (49).…”

Section: Bf Complexes With Mismatches Incorporated Into the Primer-tementioning

confidence: 99%

Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis

Wang

Hellinga²,

Beese³

2011

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

241

276

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Even though high-fidelity polymerases copy DNA with remarkable accuracy, some base-pair mismatches are incorporated at low frequency, leading to spontaneous mutagenesis. Using high-resolution X-ray crystallographic analysis of a DNA polymerase that catalyzes replication in crystals, we observe that a C•A mismatch can mimic the shape of cognate base pairs at the site of incorporation. This shape mimicry enables the mismatch to evade the error detection mechanisms of the polymerase, which would normally either prevent mismatch incorporation or promote its nucleolytic excision. Movement of a single proton on one of the mismatched bases alters the hydrogen-bonding pattern such that a base pair forms with an overall shape that is virtually indistinguishable from a canonical, Watson-Crick base pair in double-stranded DNA. These observations provide structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis, a long-standing concept that has been difficult to demonstrate directly.crystal structure | replication fidelity | mispair | polymerase structure H igh-fidelity polymerases replicate double-stranded DNA with remarkable accuracy (1). Fidelity is achieved by a successive series of conformational changes and molecular recognition events encoded at different sites on the polymerase surface such that mismatches are either prevented from incorporating or are excised within a few nucleotides past their incorporation point (2-5). At the site of covalent incorporation, shape complementarity between the polymerase surface and the edges of correctly paired bases is the dominant mechanism that determines specificity (6, 7). Here, mismatched base pairs or lesions that do not conform to this stereochemical constraint misalign their incoming triphosphate moiety relative to the 3′ OH of the growing primer terminus, leading to rejection of the incorrect or damaged nucleotides (2-4). However, modified bases that maintain the stereochemistry of cognate base-pair edges are readily incorporated (6-8). Nevertheless, polymerases do incorporate mismatched nucleotide base pairs at low frequency, leading to spontaneous mutagenesis (1).The mechanism by which spontaneous replication errors occur has long been the subject of intense speculation. In their second paper on the structure of DNA, Watson and Crick recognized that tautomerization alters the hydrogen-bonding patterns and therefore could enable mismatches to assume the structure of canonical base pairs (9). This notion was elaborated in the rare tautomer hypothesis of spontaneous mutagenesis, which states that mutations arise through the formation of high-energy tautomers at low frequency (8, 10). However, it has been challenging to obtain direct structural evidence for this mechanism. In the absence of polymerase, mismatches do not adopt a canonical base-pair structure in DNA (5, 11). Recently, a T•G mismatch has been observed to adopt a canonical base-pair structure in a polymerase, due to an ionization event, demonstrating that noncanonical hydrogen-bonding patt...

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Structural diversity of the Y-family DNA polymerases

Cited by 82 publications

References 82 publications

Lesion-Induced Mutation in the Hyperthermophilic Archaeon Sulfolobus acidocaldarius and Its Avoidance by the Y-Family DNA Polymerase Dbh

Lesion-Induced Mutation in the Hyperthermophilic Archaeon Sulfolobus acidocaldarius and Its Avoidance by the Y-Family DNA Polymerase Dbh

1H, 13C, and 15N backbone resonance assignments of the full-length 40 kDa S. acidocaldarius Y-family DNA polymerase, dinB homolog

Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis

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