title: Polymerase ζ Activity Is Linked to Replication Timing in Humans: Evidence from Mutational Signatures.
abstract: 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 ζ), 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 ζ is strongly biased toward GC→AA/TT DNMs. Using primate divergence data, we show that the GC→AA/TT pol ζ 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 ζ signature drastically increases with the replication time in the human genome. Finally, the pol ζ 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 ζ activity. This study uncovers the genomic preferences of pol ζ, shedding light on a novel cause of mutational heterogeneity along the genome.
authors.affiliation: Institute of Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia Pirogov Russian National Research Medical University, Moscow, Russia pamjat@mail.ru ruslansoldatov@gmail.com.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Seplyarskiy
authors.affiliation: Institute of Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia Pirogov Russian National Research Medical University, Moscow, Russia pamjat@mail.ru ruslansoldatov@gmail.com.
authors.forename: Georgii A
authors.initials: GA
authors.lastname: Bazykin
authors.affiliation: Institute of Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia pamjat@mail.ru ruslansoldatov@gmail.com.
authors.forename: Ruslan A
authors.initials: RA
authors.lastname: Soldatov
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D018900:Dinucleotide Repeats; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D017354:Point Mutation; D011323:Primates; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: C425929:DNA polymerase zeta; D004259:DNA-Directed DNA Polymerase
keywords: HRAS; amyotrophic lateral sclerosis; mutation rate; polymerase zeta; replication timing; transcription