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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

“On the fly” TLS on a leading strand template. An unrepaired UV-induced lesion ( ) encountered in a leading strand template leads to stalling of the replication fork downstream of the lesion (as depicted in Figure 5). TLS on a leading strand template can occur by one of two pathways. In “on the fly” TLS, bypass of the UV-induced lesion occurs before progression of the replication fork has been re-started through a re-priming event, as follows: 1) One or more TLS pols bypass the offending DNA lesion, extending the aborted primer terminus to an undamaged section of the leading strand template. 2) Pol δ faithfully extends the primer to the stalled CMG helicase where 3) the bound pol ε rapidly replaces pol δ on the leading strand template, re-starting progression of the stalled replication fork. In this scenario, replication fork re-start requires TLS. As an alternative to “on the fly” TLS, UV-induced lesions within a leading strand template may be bypassed by postreplicative gap-filling (Figure 8).

Inline graphic — “On the fly” TLS on a leading strand template. An unrepaired UV-induced lesion ( ) encountered in a leading strand template leads to stalling of the replication fork downstream of the lesion (as depicted in Figure 5). TLS on a leading strand template can occur by one of two pathways. In “on the fly” TLS, bypass of the UV-induced lesion occurs before progression of the replication fork has been re-started through a re-priming event, as follows: 1) One or more TLS pols bypass the offending DNA lesion, extending the aborted primer terminus to an undamaged section of the leading strand template. 2) Pol δ faithfully extends the primer to the stalled CMG helicase where 3) the bound pol ε rapidly replaces pol δ on the leading strand template, re-starting progression of the stalled replication fork. In this scenario, replication fork re-start requires TLS. As an alternative to “on the fly” TLS, UV-induced lesions within a leading strand template may be bypassed by postreplicative gap-filling (Figure 8).