Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair

Roy, Upasana; Schärer, Orlando D.

doi:10.1016/j.dnarep.2016.05.004

Cited by 64 publications

(71 citation statements)

References 82 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure 1) (10), and previous biochemical studies showed that translesion synthesis across DNA interstrand cross-link lesions depends highly on their structures. For instance, Ho et al.…”

Section: Discussionsupporting

confidence: 62%

Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells

Price¹,

Li²,

Gates³

et al. 2017

Nucleic Acids Research

View full text Add to dashboard Cite

Apurinic/apyrimidinic (AP) sites, or abasic sites, which are a common type of endogenous DNA damage, can forge interstrand DNA–DNA cross-links via reaction with the exocyclic amino group on a nearby 2΄-deoxyguanosine or 2΄-deoxyadenosine in the opposite strand. Here, we utilized a shuttle vector method to examine the efficiency and fidelity with which a reduced dG–AP cross-link-containing plasmid was replicated in cultured human cells. Our results showed that the cross-link constituted strong impediments to DNA replication in HEK293T cells, with the bypass efficiencies for the dG- and AP-containing strands being 40% and 20%, respectively. While depletion of polymerase (Pol) η did not perturb the bypass efficiency of the lesion, the bypass efficiency was markedly reduced (to 1–10%) in the isogenic cells deficient in Pol κ, Pol ι or Pol ζ, suggesting the mutual involvement of multiple translesion synthesis polymerases in bypassing the lesion. Additionally, replication of the cross-linked AP residue in HEK293T cells was moderately error-prone, inducing a total of ∼26% single-nucleobase substitutions at the lesion site, whereas replication past the cross-linked dG component occurred at a mutation frequency of ∼8%. Together, our results provided important insights into the effects of an AP-derived interstrand cross-link on the efficiency and accuracy of DNA replication in human cells.

show abstract

“…Figure 1) (10), and previous biochemical studies showed that translesion synthesis across DNA interstrand cross-link lesions depends highly on their structures. For instance, Ho et al.…”

Section: Discussionsupporting

confidence: 62%

Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells

Price¹,

Li²,

Gates³

et al. 2017

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Avoidance of double-strand break formation in the glycosylase-dependent unhooking mechanism eliminates the need to engage homologous recombination, a process that is quite complex in its own right and can lead to insertions and deletions in the genome [69, 123]. Both the incision-dependent (Fanconi) and incision-independent cross-link repair pathways include error-prone, potentially mutagenic steps [64, 65, 124], involving the bypass of psoralen adduct remnants [62, 63, 125, 126] and/or Ap sites [127, 128]. …”

Section: Comparison Of Incision-dependent and Incision-independentmentioning

confidence: 99%

A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

et al. 2017

View full text Add to dashboard Cite

Interstrand DNA-DNA cross-links are highly toxic lesions that are important in medicinal chemistry, toxicology, and endogenous biology. In current models of replication-dependent repair, stalling of a replication fork activates the Fanconi anemia pathway and cross-links are “unhooked” by the action of structure-specific endonucleases such as XPF-ERCC1 that make incisions flanking the cross-link. This process generates a double-strand break, which must be subsequently repaired by homologous recombination. Recent work provided evidence for a new, incision-independent unhooking mechanism involving intrusion of a base excision repair (BER) enzyme, NEIL3, into the world of cross-link repair. The evidence suggests that the glycosylase action of NEIL3 unhooks interstrand cross-links derived from an abasic site or the psoralen derivative trioxsalen. If the incision-independent NEIL3 pathway is blocked, repair reverts to the incision-dependent route. In light of the new model invoking participation of NEIL3 in cross-link repair, we consider the possibility that various BER glycosylases or other DNA-processing enzymes might participate in the unhooking of chemically diverse interstrand DNA cross-links.

show abstract

“…The replacement of N7-guanine with carbon introduces changes in hydration and charge localization (75). However, 7-deazaguanine-containing DNA has essentially the same structure as native DNA (76), and 7-deazaguanine mimics have been successfully used in a number of previous studies of DNA lesion repair and polymerase bypass (27,(77)(78)(79).…”

mentioning

confidence: 99%

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Wickramaratne

Mukherjee

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

DNA-protein cross-links (DPCs) are bulky DNA lesions that form both endogenously and following exposure to bis-electrophiles such as common antitumor agents. The structural and biological consequences of DPCs have not been fully elucidated due to the complexity of these adducts. The most common site of DPC formation in DNA following treatment with bis-electrophiles such as nitrogen mustards and cisplatin is the N7 position of guanine, but the resulting conjugates are hydrolytically labile and thus are not suitable for structural and biological studies. In this report, hydrolytically stable structural mimics of N7-guanine-conjugated DPCs were generated by reductive amination reactions between the Lys and Arg side chains of proteins/peptides and aldehyde groups linked to 7-deazaguanine residues in DNA. These model DPCs were subjected to in vitro replication in the presence of human translesion synthesis DNA polymerases. DPCs containing full-length proteins (11-28 kDa) or a 23-mer peptide blocked human polymerases and . DPC conjugates to a 10-mer peptide were bypassed with nucleotide insertion efficiency 50 -100-fold lower than for native G. Both human polymerase (hPol) and hPol inserted the correct base (C) opposite the 10-mer peptide cross-link, although small amounts of T were added by hPol . Molecular dynamics simulation of an hPol ternary complex containing a template-primer DNA with dCTP opposite the 10-mer peptide DPC revealed that this bulky lesion can be accommodated in the polymerase active site by aligning with the major groove of the adducted DNA within the ternary complex of polymerase and dCTP.

show abstract

Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair

Cited by 64 publications

References 82 publications

Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells

Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells

A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Contact Info

Product

Resources

About