The Experts below are selected from a list of 564 Experts worldwide ranked by ideXlab platform

Satya Prakash - One of the best experts on this subject based on the ideXlab platform.

  • human dna polymerase ι incorporates dctp opposite template g via a g c Hoogsteen Base Pair
    Structure, 2005
    Co-Authors: Deepak T Nair, Robert E Johnson, Louise Prakash, Satya Prakash, Aneel K Aggarwal
    Abstract:

    Summary Human DNA polymerase ι (hPolι), a member of the Y family of DNA polymerases, differs in remarkable ways from other DNA polymerases, incorporating correct nucleotides opposite template purines with a much higher efficiency and fidelity than opposite template pyrimidines. We present here the crystal structure of hPolι bound to template G and incoming dCTP, which reveals a G.C+ Hoogsteen Base Pair in a DNA polymerase active site. We show that the hPolι active site has evolved to favor Hoogsteen Base Pairing, wherein the template sugar is fixed in a cavity that reduces the C1′-C1′ distance across the nascent Base Pair from ∼10.5 A in other DNA polymerases to 8.6 A in hPolι. The rotation of G from anti to syn is then largely in response to this curtailed C1′-C1′ distance. A G.C+ Hoogsteen Base Pair suggests a specific mechanism for hPolι's ability to bypass N 2 -adducted guanines that obstruct replication.

  • distinct mechanisms of cis syn thymine dimer bypass by dpo4 and dna polymerase η
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: R E Johnson, Louise Prakash, Satya Prakash
    Abstract:

    UV-light-induced cyclobutane pyrimidine dimers (CPDs) present a severe block to synthesis by replicative DNA polymerases (Pols), whereas Polη promotes proficient and error-free replication through CPDs. Although the archael Dpo4, which, like Polη, belongs to the Y family of DNA Pols, can also replicate through a CPD, it is much less efficient than Polη. The x-ray crystal structure of Dpo4 complexed with either the 3′-thymine (T) or the 5′ T of a cis-syn TT dimer has indicated that, whereas the 3′ T of the dimer forms a Watson–Crick Base Pair with the incoming dideoxy ATP, the 5′ T forms a Hoogsteen Base Pair with the dideoxy ATP in syn conformation. Based upon these observations, a similar mechanism involving Hoogsteen Base Pairing of the 5′ T of the dimer with the incoming A has been proposed for Polη. Here we examine the mechanisms of CPD bypass by Dpo4 and Polη using nucleotide analogs that specifically disrupt the Hoogsteen or Watson–Crick Base Pairing. Our results show that both Dpo4 and Polη incorporate dATP opposite the 5′ T of the CPD via Watson–Crick Base Pairing and not by Hoogsteen Base Pairing. Furthermore, opposite the 3′ T of the dimer, the two Pols differ strikingly in the mechanisms of dATP incorporation, with Dpo4 incorporating opposite an abasic-like intermediate and Polη using the normal Watson–Crick Base Pairing. These observations have important implications for the mechanisms used for the inefficient vs. efficient bypass of CPDs by DNA Pols.

Thomas A Kunkel - One of the best experts on this subject based on the ideXlab platform.

  • preferential cis syn thymine dimer bypass by dna polymerase η occurs with biased fidelity
    Nature, 2004
    Co-Authors: Scott D Mcculloch, Robert J Kokoska, Chikahide Masutani, Shigenori Iwai, Fumio Hanaoka, Thomas A Kunkel
    Abstract:

    Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision rePair (NER)1,2. Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol η copies thymine dimers and the flanking Bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol η to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol η bypasses a dimer with low fidelity and with higher error rates at the 3′ thymine than at the 5′ thymine. A similar bias is seen with Sulfolobus solfataricus DNA polymerase 4, which forms a Watson–Crick Base Pair at the 3′ thymine of a dimer but a Hoogsteen Base Pair at the 5′ thymine (ref. 3). Ultraviolet-induced mutagenesis is also higher at the 3′ Base of dipyrimidine sequences4,5,6. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.

Sik Lok Lam - One of the best experts on this subject based on the ideXlab platform.

  • Effect of 1-methyladenine on thermodynamic stabilities of double-helical DNA structures.
    FEBS Letters, 2009
    Co-Authors: Hao Yang, Sik Lok Lam
    Abstract:

    Abstract 1-Methyladenine (m1A) alters T·A Watson–Crick to T·m1A Hoogsteen Base Pair. Owing to its conversion to N6-methyladenine (m6A) at higher temperatures, thermodynamic studies of m1A-containing DNAs using conventional melting methods are subject to the influence of m6A species. In this study, we applied nuclear magnetic resonance spectroscopy to determine the Base Pairing modes and effect of m1A on thermodynamic stability of double-helical DNA. The observed Base Pairing modes account for the destabilizing trend which follows the order T·m1A ∼ G·m1A

  • Effect of 1-methyladenine on double-helical DNA structures.
    FEBS Letters, 2008
    Co-Authors: Hao Yang, Yingqian Zhan, Dickson Fenn, Lai Man Chi, Sik Lok Lam
    Abstract:

    Methylation at the N1 site of adenine leads to the formation of cytotoxic 1-methyladenine (m1A). Since the N1 site of adenine is involved in the hydrogen bonding of T·A and A·T Watson–Crick Base Pairs, it is expected that the Pairing interactions will be disrupted upon 1-methylation. In this study, high-resolution NMR investigations were performed to determine the effect of m1A on double-helical DNA structures. Interestingly, instead of disrupting hydrogen bonding, we found that 1-methylation altered the T·A Watson–Crick Base Pair to T(anti)·m1A(syn) Hoogsteen Base Pair, providing insights into the observed differences in AlkB-rePair efficiency between dsDNA and ssDNA.

Scott D Mcculloch - One of the best experts on this subject based on the ideXlab platform.

  • preferential cis syn thymine dimer bypass by dna polymerase η occurs with biased fidelity
    Nature, 2004
    Co-Authors: Scott D Mcculloch, Robert J Kokoska, Chikahide Masutani, Shigenori Iwai, Fumio Hanaoka, Thomas A Kunkel
    Abstract:

    Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision rePair (NER)1,2. Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol η copies thymine dimers and the flanking Bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol η to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol η bypasses a dimer with low fidelity and with higher error rates at the 3′ thymine than at the 5′ thymine. A similar bias is seen with Sulfolobus solfataricus DNA polymerase 4, which forms a Watson–Crick Base Pair at the 3′ thymine of a dimer but a Hoogsteen Base Pair at the 5′ thymine (ref. 3). Ultraviolet-induced mutagenesis is also higher at the 3′ Base of dipyrimidine sequences4,5,6. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.

Hao Yang - One of the best experts on this subject based on the ideXlab platform.

  • Effect of 1-methyladenine on thermodynamic stabilities of double-helical DNA structures.
    FEBS Letters, 2009
    Co-Authors: Hao Yang, Sik Lok Lam
    Abstract:

    Abstract 1-Methyladenine (m1A) alters T·A Watson–Crick to T·m1A Hoogsteen Base Pair. Owing to its conversion to N6-methyladenine (m6A) at higher temperatures, thermodynamic studies of m1A-containing DNAs using conventional melting methods are subject to the influence of m6A species. In this study, we applied nuclear magnetic resonance spectroscopy to determine the Base Pairing modes and effect of m1A on thermodynamic stability of double-helical DNA. The observed Base Pairing modes account for the destabilizing trend which follows the order T·m1A ∼ G·m1A

  • Effect of 1-methyladenine on double-helical DNA structures.
    FEBS Letters, 2008
    Co-Authors: Hao Yang, Yingqian Zhan, Dickson Fenn, Lai Man Chi, Sik Lok Lam
    Abstract:

    Methylation at the N1 site of adenine leads to the formation of cytotoxic 1-methyladenine (m1A). Since the N1 site of adenine is involved in the hydrogen bonding of T·A and A·T Watson–Crick Base Pairs, it is expected that the Pairing interactions will be disrupted upon 1-methylation. In this study, high-resolution NMR investigations were performed to determine the effect of m1A on double-helical DNA structures. Interestingly, instead of disrupting hydrogen bonding, we found that 1-methylation altered the T·A Watson–Crick Base Pair to T(anti)·m1A(syn) Hoogsteen Base Pair, providing insights into the observed differences in AlkB-rePair efficiency between dsDNA and ssDNA.