Figure 1.

Graphical representation of the PRR pathway. The diagram shows the main steps of the PRR pathway concerning the covalent modification of PCNA (mono- and poly-ubiquitylation) in response to UV-induced damage. For simplicity, in the diagram the replication fork is represented just by its PCNA component. UV radiation can induce lesions on DNA (represented as a gray triangle in step (a)), which cause the stall of the replication fork (denoted by PCNAon)(steps (b, c), corresponding to reaction 1 in Table 3). Afterwards, PCNA is mono-ubiquitylated (PCNAon:U) by the combined activity of E2 Rad6 and E3 Rad18 (steps (d, e, f), corresponding to reactions 2 to 10 in Table 3). At this stage, mono-ubiquitylated PCNA can activate the Translesion DNA Synthesis sub-pathway (TLS), leading to lesion bypass (represented as an orange triangle in step (g), corresponding to reaction 23 in Table 3), and eventually to the ubiquitylation signal switch-off (PCNAoff). On the other hand, mono-ubiquitylated PCNA can undergo further ubiquitylation events through the combined action of E2 Ubc13-Mms2 and E3 Rad5 (steps (h, i, j), corresponding to reactions 11 to 16 in Table 3), adding a single ubiquitin moiety per step (step (k), corresponding to reaction 17 in Table 3, and step (l), corresponding to reaction 22 in Table 3). Di- and tri-ubiquitylated PCNA isoforms are denoted by PCNAon:U:U (k) and PCNAon:U:U:U (l), respectively. The steps for PCNA tri-ubiquitylation are not formally represented (dotted steps between (k) and (l), corresponding to reactions 18 to 20 in Table 3), being the process analogous to steps (h, i, j, k) for di-ubiquitylation. Poly-ubiquitylated PCNA promotes the lesion bypass (represented as an orange triangle in step (m), corresponding to reaction 25 in Table 3, and in step (n), corresponding to reaction 24 in Table 3) through the Template Switching sub-pathway (TS) which, eventually, leads to the ubiquitylation signal switch-off.

Amara et al. BMC Systems Biology 2013 7:24   doi:10.1186/1752-0509-7-24
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