TY - JOUR

T1 - Bypass of Methoxyamine-Adducted Abasic Sites by Eukaryotic Translesion DNA Polymerases

AU - Yudkina, Anna V.

AU - Novikova, Anna A.

AU - Stolyarenko, Anastasia D.

AU - Makarova, Alena V.

AU - Zharkov, Dmitry O.

PY - 2025/1/14

Y1 - 2025/1/14

N2 - The apurinic/apyrimidinic site (AP site) is a highly mutagenic and cytotoxic DNA lesion. Normally, AP sites are removed from DNA by base excision repair (BER). Methoxyamine (MOX), a BER inhibitor currently under clinical trials as a tumor sensitizer, forms adducts with AP sites (AP-MOX) resistant to the key BER enzyme, AP endonuclease. As AP-MOX remains unrepaired, translesion DNA synthesis is expected to be the main mechanism of cellular response to this lesion. However, the mutagenic potential of AP-MOX is still unclear. Here, we compare the blocking and mutagenic properties of AP-MOX and the natural AP site for major eukaryotic DNA polymerases involved in translesion synthesis: DNA polymerases η, ι, ζ, Rev1, and primase–polymerase PrimPol. The miscoding properties of both abasic lesions remained mostly the same for each studied enzyme. In contrast, the blocking properties of AP-MOX compared to the AP site were DNA polymerase specific. Pol η and PrimPol bypassed both lesions with the same efficiency. The bypass of AP-MOX by Pol ι was 15-fold lower than that of the AP site. On the contrary, Rev1 bypassed AP-MOX 5-fold better than the AP site. Together, our data suggest that Rev1 is best suited to support synthesis across AP-MOX in human cells.

AB - The apurinic/apyrimidinic site (AP site) is a highly mutagenic and cytotoxic DNA lesion. Normally, AP sites are removed from DNA by base excision repair (BER). Methoxyamine (MOX), a BER inhibitor currently under clinical trials as a tumor sensitizer, forms adducts with AP sites (AP-MOX) resistant to the key BER enzyme, AP endonuclease. As AP-MOX remains unrepaired, translesion DNA synthesis is expected to be the main mechanism of cellular response to this lesion. However, the mutagenic potential of AP-MOX is still unclear. Here, we compare the blocking and mutagenic properties of AP-MOX and the natural AP site for major eukaryotic DNA polymerases involved in translesion synthesis: DNA polymerases η, ι, ζ, Rev1, and primase–polymerase PrimPol. The miscoding properties of both abasic lesions remained mostly the same for each studied enzyme. In contrast, the blocking properties of AP-MOX compared to the AP site were DNA polymerase specific. Pol η and PrimPol bypassed both lesions with the same efficiency. The bypass of AP-MOX by Pol ι was 15-fold lower than that of the AP site. On the contrary, Rev1 bypassed AP-MOX 5-fold better than the AP site. Together, our data suggest that Rev1 is best suited to support synthesis across AP-MOX in human cells.

KW - DNA damage

KW - DNA polymerases

KW - DNA replication

KW - abasic sites

KW - methoxyamine

KW - translesion synthesis

UR - https://www.mendeley.com/catalogue/08c68124-1280-3609-9bea-b013aa08d7c9/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85216264344&origin=inward&txGid=727a4db00b7790c0df250a56dc34f153

UR - https://pubmed.ncbi.nlm.nih.gov/39859356/

UR - https://pmc.ncbi.nlm.nih.gov/articles/PMC11766430/

U2 - 10.3390/ijms26020642

DO - 10.3390/ijms26020642

M3 - Article

C2 - 39859356

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 2

M1 - 642

ER -