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Histone H4 LRS mutations can attenuate UV mutagenesis without affecting PCNA ubiquitination or sumoylation.

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UV is a significant environmental agent that damages DNA. Translesion synthesis (TLS) is a DNA damage tolerance pathway that utilizes specialized DNA polymerases to replicate through the damaged DNA, often… Click to show full abstract

UV is a significant environmental agent that damages DNA. Translesion synthesis (TLS) is a DNA damage tolerance pathway that utilizes specialized DNA polymerases to replicate through the damaged DNA, often leading to mutagenesis. In eukaryotic cells, genomic DNA is organized into chromatin that is composed of nucleosomes. To date, if and/or how TLS is regulated by a specific nucleosome feature has been undocumented. We found that mutations of multiple histone H4 residues mostly or entirely embedded in the nucleosomal LRS (loss of ribosomal DNA-silencing) domain attenuate UV mutagenesis in Saccharomyces cerevisiae. The attenuation is not caused by an alteration of ubiquitination or sumoylation of PCNA (proliferating cell nuclear antigen), the modifications well-known to regulate TLS. Also, the attenuation is not caused by decreased chromatin accessibility, or by alterations of methylation of histone H3 K79, which is at the center of the LRS surface. The attenuation may result from compromised TLS by both DNA polymerases ζ and η, in which Rad6 and Rad5 are but Rad18 is not implicated. We propose that a feature of the LRS is recognized or accessed by the TLS machineries either during/after a nucleosome is disassembled in front of a lesion-stalled replication fork, or during/before a nucleosome is reassembled behind a lesion-stalled replication fork.

Keywords: dna; tls; ubiquitination sumoylation; histone; attenuate mutagenesis

Journal Title: DNA repair
Year Published: 2020

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