Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • NEIL interacts with many DNA replication

    2022-04-12

    NEIL1 interacts with many DNA replication proteins including flap-endonuclease 1 (FEN-1), proliferating cell nuclear antigen (PCNA), and Werner RecQ helicase (WRN) through its disordered C-terminal part. One study showed that in in vitro condition, NEIL1 binds to the damaged tachykinin receptor in an RPA-coated single stranded DNA template without removing the base and cleaving the DNA strand, and blocks primer elongation by the DNA polymerase δ (Polδ). This strongly conveys that the NEIL1 stops the DNA replication at damaged site and provides signal for the repair of damage before replication (Hegdea et al., 2013).
    Structure of NEIL1 NEIL1 protein is consist of two domains (N-terminal and C-terminal domain) connected by a linker. The N-terminal domain consists of an α-helix (αA (4–18)) followed by a two-layers of β-sandwich. Each layer is composed of four antiparallel β-strands (β1(23–29 a.a.), β2(41–52 a.a.), β3(55–62 a.a.), β4(73–78 a.a.), β5(84–89 a.a.), β6(97–102 a.a.), β7 (110–115 a.a.), β8 (122–125 a.a.)). The C-terminal domain is mostly helical. It consists of seven α-helices (αB (141–150 a.a.), αC (161–164 a.a.), αD (176–186 a.a.), αE (194–198 a.a.), αF (212–218 a.a.), αG (225–240 a.a.), αH (249–259 a.a.)), two of which are involved in the H2TH motif (helices C and D). Two antiparallel β-strands (β9 (269–272 a.a.), and β10 (278–281 a.a.)) form a structural motif mimicking an antiparallel β-hairpin zinc finger but zinc is absent. The dimensions of the molecule are approximately 60×35×25Å3. The structural similarity shows that NEIL1 is closer to Thermus thermophilus Fpg than to EcoNei, while phylogenetic tree construction indicates that human NEIL1 shares a latest ancestor with EcoNei than with TthFpg. The crystal structure of NEIL1 is almost same as E. coli Nei except the zinc finger. NEIL1 contains a structural motif that mimics an antiparallel β-hairpin zinc finger. NEIL1 lacks two loops that ligate the zinc atom in bacterial Fpg and Nei but contains two β-strands (β9 and β10) that superimpose nicely onto those of EcoNei and TthFpg. The zincless finger is important for its activity and contains highly conserved arginine residue at position 277 present at the end of β-hairpin loop. Mutation of Arg-277 in NEIL1 CΔ56 showed a marked decrease in glycosylase activity whereas the lyase activity was similar to that of wild type (Doublie et al., 2004). It is assumed that this arginine might be involved in the interaction with DNA and therefore, critical for glycosylase activity. This confirms the importance of Arg-277 and that of the zincless finger in the glycosylase activity. The guanidinium group of the corresponding arginine (Arg-253) in EcoNei interacts with the phosphates on both sides of the DNA damage site. Mutation of this residue (R253A) was found to be defective in removing 5.6-dihydrouracil-containing DNA whereas its activity on abasic sites was similar to wild type (Doublie et al., 2004). NEIL1 structure contains conserved DNA-binding motif which are helix-two turn helix (H2TH), N-terminal peptide PE(G/L)P(E/ L) and an essential Lys at position 54 Hazraa et al., 2007. It has a supple interacting region within its C-terminal domain (between residues 289 and 350) that interacts with specific structural domains of Pol β (N-terminal 140 a.a. residues) and Lig IIIα (C-terminal 175 residues) (Wiederhold et al., 2004). The secondary structure of NEIL1 with essential regions is illustrated in Fig. 3. NEIL1 structure also contains a unique 19 residue insertion of residues 204–222 which comprises helix αF (Fig. 3). This unique insertion is found only in vertebrates and might play a role in the interaction with protein of the pathway, such as DNA ligIII, Pol β, or XRCC1. The crystal structure of uncomplexed NEIL1 is reported to be present in “closed” conformation and is superimposable onto either DNA-bound EcoNei or uncomplexed TthFpg structures (Doublie et al., 2004).