Elsevier

DNA Repair

Volume 95, November 2020, 102959
DNA Repair

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

https://doi.org/10.1016/j.dnarep.2020.102959Get rights and content

Highlights

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.

Section snippets

INTRODUCTION

Cells are equipped with multiple pathways, including cell cycle checkpoints, DNA repair, and damage tolerance, to reduce the deleterious consequences of DNA damage caused by endogenous and exogenous agents [1,2]. Ultraviolet (UV) is a significant DNA-damaging agent that primarily produces cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In eukaryotic cells, postreplication repair (PRR) is a Rad6-dependent DNA damage tolerance pathway that is activated when single-stranded

Plasmids and yeast strains

Plasmids and yeast strains expressing wild type histones used in this study are shown in Supplementary Tables S1 and S2, respectively. Histone H4 LRS mutants and their isogenic wild strains were created by transforming the pDM9-bearing strains (Supplementary Table S2) with pHTF2-derivatived plasmids, which express wild type histone H3 and histone H4 LRS mutants (Supplementary Table S1) and pHTF2, which expresses wild type histones H3 and H4. Plasmid pDM9 was then removed from the transformed

Histone H4 LRS mutations can attenuate UV mutagenesis

Through random mutagenesis, we identified multiple UV sensitive or resistant histone H4 mutations in the nucleosomal LRS domain (Fig. 1) [31]. We found that the histone H4 H75E mutation significantly attenuates global genomic NER and Rad26-independent transcription-coupled NER. However, all the other mutations do not significantly affect NER or a NER subpathway [31], indicating that most of the LRS mutations may be implicated in other DNA repair and/or damage tolerance pathways.

To determine if

DISCUSSION

We showed that histone H4 LRS mutations can attenuate UV mutagenesis without affecting ubiquitination or sumoylation of PCNA. Instead of being located on the nucleosome surface, all of the UV mutagenesis-deficient LRS mutations are mostly or entirely embedded in the nucleosome (Fig. 1, Fig. 2). Therefore, the TLS machinery may not recognize or access a feature of the LRS when the nucleosome is intact. Instead, the LRS feature may be recognized or accessed during/after a nucleosome is

CRediT authorship contribution statement

Kathiresan Selvam: Conceptualization, Data curation. Sheikh Arafatur Rahman: Conceptualization, Data curation. Derek Forrester: . Adam Bao: . Michael Lieu: . Shisheng Li: Conceptualization, Investigation.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

We thank Wenzhi Gong for discussion and help during the course of this study. This work was supported by NSF Grant MCB-1615550 from the National Science Foundation.

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    • 1

    These authors contributed equally to this work.

    2

    Present address: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA.

    3

    Present address: Department of Pathobiology, Faculty of Veterinary Medicine and Animal Science, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur-1706, Bangladesh.

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