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