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Georgia Institute of Technology

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Nucleic Acids Res., Dec 20 2023, gkad1204 | https://doi.org/10.1093/nar/gkad1204 Light-strand bias and enriched zones of embedded ribonucleotides are associated with DNA replication and transcription in the human-mitochondrial genome

Penghao Xu ¹, Taehwan Yang ¹, Deepali L Kundnani ¹, Mo Sun ¹, Stefania Marsili ¹, Alli L Gombolay ¹, Youngkyu Jeon ¹, Gary Newnam ¹, Sathya Balachander¹, Veronica Bazzani ^2,3, Umberto Baccarani ^2,4, Vivian S Park ⁵, Sijia Tao ⁶, Adriana Lori ^7,8, Raymond F Schinazi ⁶, Baek Kim⁶, Zachary F Pursell ⁵, Gianluca Tell ⁹, Carlo Vascotto ^2,3, Francesca Storici ¹

¹School of Biological Sciences, Georgia Institute of Technology, Atlanta 30332, GA, USA.

²Department of Medicine, University of Udine, Udine 33100, Italy.

³IMol Polish Academy of Sciences, Warsaw 02-247, Poland.

⁴General Surgery Clinic and Liver Transplant Center, University-Hospital of Udine, Udine 33100, Italy.

⁵Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University of Medicine, New Orleans, LA 70118, USA.

⁶Center for ViroScience and Cure, Department of Pediatrics, Laboratory of Biochemical Pharmacology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta 30322, GA, USA.

⁷Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta 30329, GA, USA.

⁸Department of Population Science, American Cancer Society, Kennesaw 30144, GA, USA.

⁹Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine 33100, Italy.

The first two authors should be regarded as Joint First Authors.

To whom correspondence should be addressed. : Francesca Storici

Abstract

Abundant ribonucleoside-triphosphate (rNTP) incorporation into DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA-structural change and genome instability. The rNMP distribution, characteristics, hotspots and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in hmtDNA of six different cell types. In most cell types, the rNMPs are preferentially embedded on the light strand of hmtDNA with a strong bias towards rCMPs; while in the liver-tissue cells, the rNMPs are predominately found on the heavy strand. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the control region, which links the rNMP presence to the frequent hmtDNA replication-failure events. We show a strong correlation between coding-sequence size and rNMP-embedment frequency per nucleotide on the non-template, light strand in all cell types, supporting the presence of transient RNA-DNA hybrids preceding light-strand replication. Moreover, we detect rNMP-embedment patterns that are only partly conserved across the different cell types and are distinct from those found in yeast mtDNA. The study opens new research directions to understand the biology of hmtDNA and genomic rNMPs.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2024-01-11)
연구진국외 연구진
분야 생명과학 > 분자생물학

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