ライフサイエンスコーパス: Pol zeta

1 Pol zeta is an error-prone DNA polymerase that is critic

2 Pol zeta is particularly error prone for substitutions i

3 Pol zeta is relatively accurate for single base insertio

4 Pol zeta is unique amongst TLS polymerases for its essen

5 Pol zeta is very inefficient in inserting deoxynucleotid

6 Pol zeta, however, is unusually sensitive to geometric d

7 Pol zeta-deficient B cells had a reduction in mutation f

8 tional knockout and a knock-in strain with a Pol zeta mutagenesis-enhancing mutation.

9 he assembly of the [4Fe-4S] cluster abrogate Pol zeta function in UV mutagenesis.

10 With a tagged form of an active Pol zeta variant, we isolated two additional accessory s

11 s occur by the exchange of the Pol delta and Pol zeta catalytic subunits on a preassembled complex of

12 similar C-terminal domains of Pol delta and Pol zeta contain a [4Fe-4S] cluster coordinated by four

13 Both Pol eta and Pol zeta extended the DL more efficiently than Pol delta

14 ra indicates a hierarchy between Pol eta and Pol zeta with respect to the bypass of UV-induced lesion

15 and DNA polymerase (Pol) delta, Pol eta, and Pol zeta.

16 Additionally, Pol eta, Pol iota, and Pol zeta, but not Pol kappa, had important roles in prom

17 Also, we provide evidence that Pol kappa and Pol zeta function together in promoting error-free repli

18 s deoxynucleotides opposite DNA lesions, and Pol zeta functions as a mispair extender.

19 ation fork to generate a first mutation, and Pol zeta extends the mismatch with a second mutation.

20 eracts with Y-type DNA polymerases (Pol) and Pol zeta to bypass many types of adducts that block the

21 died the ability of Y-family polymerases and Pol zeta to bypass ICLs that induce different degrees of

22 and describe the specific roles of Rev1 and Pol zeta in handling these disturbances.

23 s mutagenesis that relies on POLD3, Rev1 and Pol zeta.

24 by reversion of the lys2deltaA746 allele, as Pol zeta produces a distinct mutational signature in thi

25 antigen (PCNA)-dependent TLS by Pol zeta as Pol zeta(2) lacks functional interactions with PCNA.

26 For all other DNA bases Pol zeta is essential for ROS-induced mutagenesis.

27 w that although Pol32 does not directly bind Pol zeta, Pol32 can bind the Rev1-Pol zeta complex throu

28 ther by Rev1 in the Rev1-Pol32 complex or by Pol zeta in the Pol zeta-Rev1-Pol32 complex, irrespectiv

29 tes are comparable with replication rates by Pol zeta on undamaged DNA.

30 gesting that low-fidelity DNA replication by Pol zeta is at least partly responsible for the MNMs tha

31 nslesion synthesis of a model abasic site by Pol zeta.

32 p did not stimulate translesion synthesis by Pol zeta or by DNA polymerase delta.

33 er termini and extension of these termini by Pol zeta.

34 cell nuclear antigen (PCNA)-dependent TLS by Pol zeta as Pol zeta(2) lacks functional interactions wi

35 required for translesion synthesis (TLS) by Pol zeta.

36 a terminus that was extended efficiently by Pol-zeta, but not by yeast Pol-alpha.

37 erein, we show that Saccharomyces cerevisiae Pol zeta binds to the Pol31 and Pol32 subunits of Pol de

38 t the properties of Saccharomyces cerevisiae Pol zeta in which phenyalanine was substituted for the c

39 The translesion polymerases Pol eta, Pol zeta, and Rev1 are part of a suite of factors in yea

40 n found to physically interact with Pol eta, Pol zeta, and Rev1, suggesting a possible role of PolDIP

41 onger version, found naturally in eukaryotic Pol zeta (a family-B translesion synthesis polymerase).

42 uirement of Rev1 as a structural element for Pol zeta and not for Pol eta, these observations have ra

43 al significance of Rev1 binding to Pol32 for Pol zeta function in TLS and suggest a structural role f

44 So far, such a role for Pol zeta has been established for cyclobutane pyrimidine

45 Furthermore, Pol zeta, but not Pol eta, also contributes to 4-NQO res

46 onsisting of the Rev1 CTD, the heterodimeric Pol zeta complex, and the Pol kappa Rev1-interacting reg

47 on of a minimally catalytically active human Pol zeta variant.

48 d two additional accessory subunits of human Pol zeta, PolD2 and PolD3.

49 Amino acid changes in Pol zeta that prevent the assembly of the [4Fe-4S] clust

50 ct or the abasic sites as those deficient in Pol zeta or Rev1.

51 o decipher the bases of Pol32 involvement in Pol zeta-mediated TLS, here we examine whether Pol32 phy

52 v1 plays an indispensable structural role in Pol zeta-dependent lesion bypass, the role of its DNA sy

53 v1 plays an indispensable structural role in Pol zeta-mediated TLS and it binds the Rev3 catalytic su

54 physical interactions with Rev3 inactivates Pol zeta function in TLS.

55 L979F Pol zeta also generates multiple errors in close proximi

56 L979F Pol zeta shares with wild-type Pol zeta the ability to p

57 Errors generated by L979F Pol zeta in vitro include single-base insertions, deleti

58 When copying undamaged DNA, L979F Pol zeta is error-prone compared to wild-type Pol zeta,

59 We show that purified L979F Pol zeta is 30% as active as wild-type Pol zeta when rep

60 Thus L979F Pol zeta, and perhaps wild-type Pol zeta, which also gen

61 At a minimum, Pol zeta consists of a catalytic subunit Rev3 and an acc

62 ches, whereas knock-in mice with a mutagenic Pol zeta displayed a marked increase in mutation frequen

63 e for Pol kappa at the insertion step and of Pol zeta at the extension step of Tg bypass.

64 l role for Rev1 in modulating the binding of Pol zeta with Pol32 in Pol delta stalled at a lesion sit

65 In addition, depletion of Pol zeta resulted in significant decreases in T-->C muta

66 er in Rev3 is essential for the formation of Pol zeta(4) and damage-induced mutagenesis.

67 ermutation, we generated two mouse models of Pol zeta function: a B cell-specific conditional knockou

68 f Pol kappa, and for O6-CMdG upon removal of Pol zeta.

69 r results, we suggest a nonredundant role of Pol zeta in DNA DSB repair through nonhomologous end joi

70 the data thus argue against a direct role of Pol zeta in SHM, Pol zeta deficiency directly interfered

71 tations that represent a unique signature of Pol zeta.

72 bstitution in Rev3, the catalytic subunit of Pol zeta, are nearly UV immutable, suggesting severe los

73 ), we ablated Rev3, the catalytic subunit of Pol zeta, selectively in mature B cells in vivo.

74 sensus motif is lacking in either subunit of Pol zeta, yet its activity is stimulated by PCNA.

75 n the gene encoding the catalytic subunit of Pol zeta.

76 S and it binds the Rev3 catalytic subunit of Pol zeta.

77 results showed that deficiency in Pol eta or Pol zeta, but not Pol kappa or Pol iota, led to pronounc

78 ic cells deficient in Pol kappa, Pol iota or Pol zeta, suggesting the mutual involvement of multiple

79 However, on its own, Pol zeta is highly inefficient at replicating through DN

80 tion is combined with that of DNA polymerase Pol zeta, which is essential for damage-induced mutagene

81 e the spectrum of the error-prone polymerase Pol zeta, suggesting that low-fidelity DNA replication b

82 resectioning and the error-prone polymerase Pol zeta.

83 with Rev1 and the error-prone TLS polymerase Pol zeta, and elevates mutagenesis that relies on POLD3,

84 generated by another error-prone polymerase, Pol zeta.

85 ly with Rev7 (a subunit of a TLS polymerase, Pol zeta) and with two other Y-family polymerases, Pol i

86 yeast translesion synthesis DNA polymerases Pol zeta and Pol eta in UV survival and mutagenesis were

87 To probe Pol zeta functions in vivo via its error signature, here

88 n indispensable structural role in promoting Pol zeta function, and deletion of the Rev1-C terminal r

89 The error-prone Pol zeta can also participate in replication of undamage

90 TLS are three DNA polymerases (Pols): Rev1, Pol zeta (Rev3/7), and Pol eta (Rad30), all with human h

91 ectly bind Pol zeta, Pol32 can bind the Rev1-Pol zeta complex through its interaction with Rev1.

92 negatively regulates POLD3 function in Rev1/Pol zeta-dependent TLS, revealing a previously unrecogni

93 ithin this group, including RAD5, REV3/REV7 (Pol zeta), RAD30 (Pol eta), and POL30 (PCNA).

94 ue against a direct role of Pol zeta in SHM, Pol zeta deficiency directly interfered with CSR in that

95 A stable Pol zeta(4) complex can be identified in all phases of t

96 fective pol30-113 mutant, fails to stimulate Pol zeta(4) activity, providing an explanation for the o

97 ubunits of Pol delta, forming a four-subunit Pol zeta(4) complex (Rev3-Rev7-Pol31-Pol32).

98 te pathways for mutagenic TLS, surprisingly, Pol zeta functions independently of these Pols and in a

99 We found that Pol zeta is very inefficient at inserting nucleotides op

100 We show that Pol zeta/Rev1-dependent mutations occur at sites of repl

101 nesis in nondividing cells occurs during the Pol zeta-dependent filling of lesion-containing, NER-gen

102 the Rev1-Pol32 complex or by Pol zeta in the Pol zeta-Rev1-Pol32 complex, irrespective of whether pro

103 e, we show that the C-terminal domain of the Pol zeta catalytic subunit interacts with accessory subu

104 that the complex events are dependent on the Pol zeta translesion polymerase, thus implicating the DN

105 se sequences that is primarily used when the Pol zeta/Rev1-dependent pathway is inactive.

106 Thus, Pol zeta is a highly specialized polymerase that can pro

107 L979F Pol zeta shares with wild-type Pol zeta the ability to perform moderately processive DN

108 L979F Pol zeta is 30% as active as wild-type Pol zeta when replicating undamaged DNA.

109 ol zeta is error-prone compared to wild-type Pol zeta, providing a biochemical rationale for the obse

110 Thus L979F Pol zeta, and perhaps wild-type Pol zeta, which also generates clustered mutations at a

111 To date, no vertebrate Pol zeta has been purified for biochemical characterizat

112 otide insertion opposite the lesion, whereas Pol zeta executes the extension step.

113 Here, we examine whether Pol zeta can replicate through the 7,8-dihydro-8-oxoguan

114 rporates a C opposite this adduct from which Pol zeta subsequently extends, thereby completing the le

115 sions occurs when Pol delta is combined with Pol zeta, indicating a role for Polzeta in extending fro

116 city of pol zeta in vitro is consistent with Pol zeta-dependent mutagenic specificity reported in viv

117 mine whether Pol32 physically interacts with Pol zeta or its associated proteins and provide evidence

118 that human Pol iota and a two-subunit yeast Pol zeta complex (REV3/REV7) could function efficiently

119 DNA polymerase zeta (Pol zeta) and Rev1 are key players in translesion DNA sy

120 DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that s

121 DNA polymerase zeta (Pol zeta) plays a key role in DNA translesion synthesis

122 DNA polymerase zeta (Pol zeta), a heterodimer of Rev3 and Rev7, is essential

123 nthesis (TLS) together with polymerase zeta (Pol zeta), comprised of the Rev3 catalytic and Rev7 acce

124 on bypass together with DNA polymerase zeta (Pol zeta).

125 roteins are subunits of DNA polymerase-zeta (Pol-zeta), an enzyme whose sole function appears to be t