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