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. Author manuscript; available in PMC: 2016 Jan 12.
Published in final edited form as: Annu Rev Genet. 2015 Nov 23;49:243–267. doi: 10.1146/annurev-genet-112414-054714

Figure 5. Mutation clusters resulting from lesions in ssDNA without an opportunity for templated repair.

Figure 5

(a) Clusters associated with 5′→3′ resection at uncapped telomeres. Step (i): The protective cap of a telomere dissociates. The uncapped telomere is recognized as a DSB and is resected to generate long 3′ ssDNA overhang. Base damage (orange stars) occurs within the exposed ssDNA, e.g., APOBEC generating uracils. Step (ii): If uracils are not excised, a replicase simply inserts adenines. Step (iii): Base excision repair excises uracils and uses the adenines to template repair, resulting in cluster of C to T transitions. Alternatively, DNA with U:A pairs can be copied without base excision repair, still producing a product with C to T transitions. Step (iv): If uracils created by C-deamination in ssDNA are excised by uracil DNA glycosylase, abasic (AP) sites are generated. Step (v): AP sites are bypassed in an error-prone manner by TLS polymerases, usually inserting either A or C across AP-sites. Step (vi): Excision repair fixes mutation cluster containing a mix of C to T transitions and C to G transversions.

(b) Clusters associated with 5′→3′ resection around a DSB. Step (i): A two-sided DSB is resected to generate 3′ ssDNA overhangs. Base damage at e.g. cytosines (base specificity shown by orange color) occurs within overhangs. Step (ii): Repair synthesis, using TLS polymerase(s) inserts bases opposite the lesions in an error-prone way. Step (iii): Excision repair fixes mutation cluster spanning the DSB region. Note the switch in base specificity of strand-coordination within these clusters.

(c) Clusters associated with ssDNA generated by break-induced replication (BIR). Step (i): The 3′ ssDNA overhang from a resected one-sided DSB invades a homologous sequence in a donor chromosome. Step (ii): Leading strand synthesis (solid arrow) proceeds, while lagging strand synthesis (dashed arrow) occurs later, exposing long stretches of ssDNA, which sustain base damage. Step (iii): Completion of lagging strand synthesis and excision repair fix mutation cluster in repaired chromosome. Note that BIR-associated clusters do not show a switch in base specificity of strand-coordination (compare (c) with (b))