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. Author manuscript; available in PMC: 2017 Oct 31.

Published in final edited form as: Chem Rev. 2017 May 12;117(12):7857–7877. doi: 10.1021/acs.chemrev.7b00046

Pol ε encountering a UV-induced lesion within a leading strand template. This model shown in cartoon form depicts discontinuous lagging strand DNA synthesis as a dashed line for simplicity. Arrows indicate the direction of DNA synthesis (5′ ➜ 3′). The heterohexameric MCM core is depicted as a barrel. (1) Upon encountering a UV-induced lesion ( ) within a leading strand template, DNA synthesis by pol ε abruptly stops but the CMG helicase remains intact and continues unwinding DNA, exposing long stretches of the leading strand template. During such uncoupling, RPA coats the exposed leading strand template and DNA synthesis continues on the undamaged lagging strand template as the replication fork progresses. Furthermore, non-replicating pol ε maintains contact with the CMG helicase and is carried downstream of the offending lesion while PCNA is left behind at the blocked P/T junction. Pol ε may also maintain contact with the blocked P/T junction upon uncoupling, forming ssDNA loop. However, such complexes are expected to be short-lived due to RPA●ssDNA interactions. (2) Uncoupled from leading strand DNA synthesis, the CMG helicase and, hence, lagging strand DNA synthesis eventually stall downstream of the offending damage, halting progression of the replication fork.

Inline graphic — Pol ε encountering a UV-induced lesion within a leading strand template. This model shown in cartoon form depicts discontinuous lagging strand DNA synthesis as a dashed line for simplicity. Arrows indicate the direction of DNA synthesis (5′ ➜ 3′). The heterohexameric MCM core is depicted as a barrel. (1) Upon encountering a UV-induced lesion ( ) within a leading strand template, DNA synthesis by pol ε abruptly stops but the CMG helicase remains intact and continues unwinding DNA, exposing long stretches of the leading strand template. During such uncoupling, RPA coats the exposed leading strand template and DNA synthesis continues on the undamaged lagging strand template as the replication fork progresses. Furthermore, non-replicating pol ε maintains contact with the CMG helicase and is carried downstream of the offending lesion while PCNA is left behind at the blocked P/T junction. Pol ε may also maintain contact with the blocked P/T junction upon uncoupling, forming ssDNA loop. However, such complexes are expected to be short-lived due to RPA●ssDNA interactions. (2) Uncoupled from leading strand DNA synthesis, the CMG helicase and, hence, lagging strand DNA synthesis eventually stall downstream of the offending damage, halting progression of the replication fork.