Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events

Umit Akkose,Veysel Ogulcan Kaya,Aziz Sancar,Zeynep Karagoz,Laura Lindsey-Boltz,Peter A Larsen,Ogun Adebali,Anne D Yoder,Adam D Brown

doi:10.1186/s12864-021-07898-3

Abstract

BackgroundNucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Correspondingly, genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. A number of XR-seq experiments at a variety of conditions for different damage types revealed heterogenous repair in the human genome. Although human repair profiles were extensively studied, how repair maps vary between primates is yet to be investigated. Here, we characterized the genome-wide UV-induced damage repair in gray mouse lemur, Microcebus murinus, in comparison to human.ResultsWe derived fibroblast cell lines from mouse lemur, exposed them to UV irradiation, and analyzed the repair events genome-wide using the XR-seq protocol. Mouse lemur repair profiles were analyzed in comparison to the equivalent human fibroblast datasets. We found that overall UV sensitivity, repair efficiency, and transcription-coupled repair levels differ between the two primates. Despite this, comparative analysis of human and mouse lemur fibroblasts revealed that genome-wide repair profiles of the homologous regions are highly correlated, and this correlation is stronger for highly expressed genes. With the inclusion of an additional XR-seq sample derived from another human cell line in the analysis, we found that fibroblasts of the two primates repair UV-induced DNA lesions in a more similar pattern than two distinct human cell lines do.ConclusionOur results suggest that mouse lemurs and humans, and possibly primates in general, share a homologous repair mechanism as well as genomic variance distribution, albeit with their variable repair efficiency. This result also emphasizes the deep homologies of individual tissue types across the eukaryotic phylogeny.

Highlights

Nucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers
global repair (GR) is active throughout the genome, whereas transcription-coupled repair (TCR) is only active on the transcribed strands as it is initiated by damage recognition through stalled RNA polymerase II (RNAPII)
Genome-level understanding of human repair behavior is relatively well established in recent years, the associations between closely related primates with respect to UV damage response and genome-wide repair distribution were entirely lacking

Summary

Introduction

Nucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. Nucleotide excision repair is an essential mechanism to remove bulky DNA adducts, including UV-induced DNA lesions [1]. Two subpathways based on damage recognition lead to two repair mechanisms: global repair (GR) and transcription-coupled repair (TCR). To reveal genomewide excision repair dynamics, heterogeneity and associations, eXcsion Repair sequencing (XR-seq) was developed. DNA lesions might preferentially form at certain local sites in the genome, the overall heterogeneity of repair is mainly due to uneven repair efficiency throughout the genome [3, 4]. Genome-wide heterogenous repair distribution is mostly caused by transcription and chromatin structure [5,6,7,8]

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