TY - JOUR

T1 - Unrepairable substrates of nucleotide excision repair and their application to suppress the activity of this repair system

AU - Popov, A. A.

AU - Evdokimov, A. N.

AU - Lukyanchikova, N. V.

AU - Petruseva, I. O.

AU - Lavrik, O. I.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - In the previous studies, the DNA with the bulky Fap-dC derivative was demonstrated to be a difficult substrate for the nucleotide excision repair (NER), a system which is involved in the removal of bulky lesions from DNA. This type of compounds could be of particular interest as possible selective NER, considerably reducing the potency of DNA repair due to competitive immobilization of protein factors involved in this process. This approach can be potentially useful to increase the efficiency of chemotherapy. Aim. To identify DNA structures containing multiple bulky adducts that can efficiently inhibit the nucleotide excision repair. Methods. Enzymatic DNA synthesis, PCR, NER-competent cell extract preparation, in vitro NER assay, HPLC. Results. The conditions for the synthesis of extended DNA containing multiple unrepairable lesions were established. A wide range of DNA structures containing modified nucleotides was obtained. All modified DNAs were shown to inhibit the in vitro activity of the NER system. The DNA structure that inhibits the NER activity with the highest efficiency was selected. Conclusions. The model DNA structures effectively inhibiting the activity of NER were found. The new data obtained here can potentially be used for both basic and applied research.

AB - In the previous studies, the DNA with the bulky Fap-dC derivative was demonstrated to be a difficult substrate for the nucleotide excision repair (NER), a system which is involved in the removal of bulky lesions from DNA. This type of compounds could be of particular interest as possible selective NER, considerably reducing the potency of DNA repair due to competitive immobilization of protein factors involved in this process. This approach can be potentially useful to increase the efficiency of chemotherapy. Aim. To identify DNA structures containing multiple bulky adducts that can efficiently inhibit the nucleotide excision repair. Methods. Enzymatic DNA synthesis, PCR, NER-competent cell extract preparation, in vitro NER assay, HPLC. Results. The conditions for the synthesis of extended DNA containing multiple unrepairable lesions were established. A wide range of DNA structures containing modified nucleotides was obtained. All modified DNAs were shown to inhibit the in vitro activity of the NER system. The DNA structure that inhibits the NER activity with the highest efficiency was selected. Conclusions. The model DNA structures effectively inhibiting the activity of NER were found. The new data obtained here can potentially be used for both basic and applied research.

KW - DNA repair

KW - Model DNA substrates

KW - Nucleotide excision repair

KW - Unrepairable DNA lesions

UR - http://www.scopus.com/inward/record.url?scp=85085565847&partnerID=8YFLogxK

U2 - 10.7124/bc.00099C

DO - 10.7124/bc.00099C

M3 - Article

AN - SCOPUS:85085565847

VL - 35

SP - 107

EP - 117

JO - Biopolymers and Cell

JF - Biopolymers and Cell

SN - 0233-7657

IS - 2

ER -