Polymerase zeta Activity Is Linked to Replication Timing in Humans: Evidence from Mutational Signatures

摘要

Replication timing is an important determinant of germline mutation patterns, with a higher rate of point mutations in late replicating regions. Mechanisms underlying this association remain elusive. One of the suggested explanations is the activity of error-prone DNA polymerases in late-replicating regions. Polymerase zeta (pol zeta), an essential error-prone polymerase biased toward transversions, also has a tendency to produce dinucleotide mutations (DNMs), complex mutational events that simultaneously affect two adjacent nucleotides. Experimental studies have shown that pol zeta is strongly biased toward GC -> AA/TT DNMs. Using primate divergence data, we show that the GC -> AA/TT pol zeta mutational signature is the most frequent among DNMs, and its rate exceeds the mean rate of other DNM types by a factor of approximately 10. Unlike the overall rate of DNMs, the pol zeta signature drastically increases with the replication time in the human genome. Finally, the pol zeta signature is enriched in transcribed regions, and there is a strong prevalence of GC -> TT over GC -> AA DNMs on the nontemplate strand, indicating association with transcription. A recurrently occurring GC -> TT DNM in HRAS and SOD1 genes causes the Costello syndrome and amyotrophic lateral sclerosis correspondently; we observe an approximately 1 kb long mutation hotspot enriched by transversions near these DNMs in both cases, suggesting a link between these diseases and pol zeta activity. This study uncovers the genomic preferences of pol zeta, shedding light on a novel cause of mutational heterogeneity along the genome.