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DNA Replication and Genetic Research: An Honorary Issue in Memory...
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DNA Replication and Genetic Research: An Honorary Issue in Memory of Prof. James L. German

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 4827

Special Issue Editors

Dr. Sudha Sharma

E-Mail Website
Guest Editor
National Human Genome Center, Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA
Interests: genome maintenance; DNA damage; DNA repair; gene regulation; cancer-predisposing syndromes; breast cancer; premature aging; helicases
Dr. Robert M. Brosh, Jr.

E-Mail Website
Guest Editor
Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
Interests: aging; age-related diseases; cancer; genetics; DNA repair; genomic instability; replication stress; helicase; genome biology; therapeutics
Special Issues, Collections and Topics in MDPI journals
Dr. Nathan A. Ellis

E-Mail Website
Guest Editor
University of Arizona Cancer Center, Tucson, AZ 85716, USA
Interests: cancer susceptibility; genomic instability; somatic mutation; replication stress; DNA helicases; cancer genetics and genomics; epigenetic regulation; colorectal cancer; cancer health disparities

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to Dr. James L. German in recognition of his remarkable contributions to the field of human genetics and chromosome biology.

Dr. James L. German was a physician and a scientist. He was an early pioneer in human genetics. Beginning in 1959, he entered human genetics through the field of cytogenetics. Dr. German discovered and characterized the chromosome instability phenotype in Bloom’s syndrome, and he established the linkage between chromosome instability and cancer predisposition. Dr. German devoted a substantial portion of his scientific career to the comprehensive characterization of the natural history of Bloom’s syndrome through the Bloom’s Syndrome Registry, which he used to investigate the clinical consequences of genomic instability. In the 1990s, Dr. German and his laboratory members identified the gene mutation in Bloom’s syndrome, which they called BLM. BLM is a member of the RecQ family of DNA helicases, which are implicated in various pathways of nucleic acid metabolism. We have since learned that the null mutations in BLM disable cells’ ability to disentangle many different substrates generated in the homologous recombination repair pathway, affecting processes in the S, G2, and mitotic phases of the cell cycle. Bloom’s syndrome represents a class of human diseases referred to as “chromosome breakage syndromes” that includes Fanconi anemia, ataxia–telangiectasia, Nijmegen breakage syndrome, Rothmund Thomson syndrome, and Werner syndrome. Remarkably, these clinically distinct human disorders are caused by mutations in genes encoding enzymes implicated in pathways of DNA replication and repair responsible for the maintenance of genomic stability.  In addition, these diseases are often associated with cancer predisposition.

To honor Professor German’s contributions to the field, this Special Issue aims to review the instrumental role of molecular genetic analyses to improve our current understanding of the pathogenesis of chromosomal instability syndromes, and the role of DNA replication and repair in chromosome integrity and cellular homeostasis. In addition, we would like to discuss the functional crosstalk between genomic instability and cancer susceptibility. In this Special Issue of Cells, we invite your contributions, in the form of original research articles or reviews, on all aspects related to recent advances in the fields of genetic diseases characterized by DNA replication defects and/or genomic instability

Dr. Sudha Sharma
Dr. Robert M. Brosh, Jr.
Dr. Nathan A. Ellis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA replication
  • genomic instability
  • BLM
  • Bloom syndrome
  • DNA damage
  • helicases: hereditary cancer predisposition syndromes, premature aging syndromes
  • DNA repair
  • RecQ
  • genetic disease
  • chromosome stability

Published Papers (4 papers)

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Research

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17 pages, 7748 KiB  
Article
SIRT1 Prevents R-Loops during Chronological Aging by Modulating DNA Replication at rDNA Loci
by Bhushan L. Thakur, Nana A. Kusi, Sara Mosavarpour, Roger Zhu, Christophe E. Redon, Haiqing Fu, Anjali Dhall, Lorinc S. Pongor, Robin Sebastian, Fred E. Indig and Mirit I. Aladjem
Cells 2023, 12(22), 2630; https://doi.org/10.3390/cells12222630 - 15 Nov 2023
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Abstract
In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication, and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant [...] Read more.
In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication, and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant origins). We studied the effects of aging and SIRT1 activity on replication origin usage and the incidence of transcription–replication collisions (creating R-loop structures) in adult human cells obtained at different time points during chronological aging and in cancer cells. In primary, untransformed cells, SIRT1 activity declined and the prevalence of R-loops rose with chronological aging. Both the reduction in SIRT1 activity and the increased abundance of R-loops were also observed during the passage of primary cells in culture. All cells, regardless of donor age or transformation status, reacted to the short-term, acute chemical inhibition of SIRT1 with the activation of excessive replication initiation events coincident with an increased prevalence of R-loops. However, cancer cells activated dormant replication origins, genome-wide, during long-term proliferation with mutated or depleted SIRT1, whereas, in primary cells, the aging-associated SIRT1-mediated activation of dormant origins was restricted to rDNA loci. These observations suggest that chronological aging and the associated decline in SIRT1 activity relax the regulatory networks that protect cells against excess replication and that the mechanisms protecting from replication–transcription collisions at the rDNA loci manifest as differentially enhanced sensitivities to SIRT1 decline and chronological aging. Full article
(This article belongs to the Special Issue DNA Replication and Genetic Research: An Honorary Issue in Memory of Prof. James L. German)
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Review

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20 pages, 4275 KiB  
Review
Variation of Structure and Cellular Functions of Type IA Topoisomerases across the Tree of Life
by Kemin Tan and Yuk-Ching Tse-Dinh
Cells 2024, 13(6), 553; https://doi.org/10.3390/cells13060553 - 21 Mar 2024
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Abstract
Topoisomerases regulate the topological state of cellular genomes to prevent impediments to vital cellular processes, including replication and transcription from suboptimal supercoiling of double-stranded DNA, and to untangle topological barriers generated as replication or recombination intermediates. The subfamily of type IA topoisomerases are [...] Read more.
Topoisomerases regulate the topological state of cellular genomes to prevent impediments to vital cellular processes, including replication and transcription from suboptimal supercoiling of double-stranded DNA, and to untangle topological barriers generated as replication or recombination intermediates. The subfamily of type IA topoisomerases are the only topoisomerases that can alter the interlinking of both DNA and RNA. In this article, we provide a review of the mechanisms by which four highly conserved N-terminal protein domains fold into a toroidal structure, enabling cleavage and religation of a single strand of DNA or RNA. We also explore how these conserved domains can be combined with numerous non-conserved protein sequences located in the C-terminal domains to form a diverse range of type IA topoisomerases in Archaea, Bacteria, and Eukarya. There is at least one type IA topoisomerase present in nearly every free-living organism. The variation in C-terminal domain sequences and interacting partners such as helicases enable type IA topoisomerases to conduct important cellular functions that require the passage of nucleic acids through the break of a single-strand DNA or RNA that is held by the conserved N-terminal toroidal domains. In addition, this review will exam a range of human genetic disorders that have been linked to the malfunction of type IA topoisomerase. Full article
(This article belongs to the Special Issue DNA Replication and Genetic Research: An Honorary Issue in Memory of Prof. James L. German)
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16 pages, 764 KiB  
Review
The Response of the Replication Apparatus to Leading Template Strand Blocks
by Marina A. Bellani, Althaf Shaik, Ishani Majumdar, Chen Ling and Michael M. Seidman
Cells 2023, 12(22), 2607; https://doi.org/10.3390/cells12222607 - 11 Nov 2023
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Abstract
Duplication of the genome requires the replication apparatus to overcome a variety of impediments, including covalent DNA adducts, the most challenging of which is on the leading template strand. Replisomes consist of two functional units, a helicase to unwind DNA and polymerases to [...] Read more.
Duplication of the genome requires the replication apparatus to overcome a variety of impediments, including covalent DNA adducts, the most challenging of which is on the leading template strand. Replisomes consist of two functional units, a helicase to unwind DNA and polymerases to synthesize it. The helicase is a multi-protein complex that encircles the leading template strand and makes the first contact with a leading strand adduct. The size of the channel in the helicase would appear to preclude transit by large adducts such as DNA: protein complexes (DPC). Here we discuss some of the extensively studied pathways that support replication restart after replisome encounters with leading template strand adducts. We also call attention to recent work that highlights the tolerance of the helicase for adducts ostensibly too large to pass through the central channel. Full article
(This article belongs to the Special Issue DNA Replication and Genetic Research: An Honorary Issue in Memory of Prof. James L. German)
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13 pages, 685 KiB  
Review
Understanding the Human RECQ5 Helicase—Connecting the Dots from DNA to Clinics
by Chiefe Mo, Yukari Shiozaki, Kenneth Omabe and Yilun Liu
Cells 2023, 12(16), 2037; https://doi.org/10.3390/cells12162037 - 10 Aug 2023
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Abstract
RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless, dysregulation of RECQ5 has emerged as a significant clinical concern, being linked to cancer predisposition, cardiovascular disease, [...] Read more.
RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless, dysregulation of RECQ5 has emerged as a significant clinical concern, being linked to cancer predisposition, cardiovascular disease, and inflammation. In cells, RECQ5 assumes a crucial role in the regulation of DNA repair pathways, particularly in the repair of DNA double-strand breaks and inter-strand DNA crosslinks. Moreover, RECQ5 exhibits a capacity to modulate gene expression by interacting with transcription machineries and their co-regulatory proteins, thus safeguarding against transcription-induced DNA damage. This review aims to provide an overview of the multifaceted functions of RECQ5 and its implications in maintaining genomic stability. We will discuss the potential effects of clinical variants of RECQ5 on its cellular functions and their underlying mechanisms in the pathogenesis of cancer and cardiovascular disease. We will review the impact of RECQ5 variants in the field of pharmacogenomics, specifically their influence on drug responses, which may pave the way for novel therapeutic interventions targeting RECQ5 in human diseases. Full article
(This article belongs to the Special Issue DNA Replication and Genetic Research: An Honorary Issue in Memory of Prof. James L. German)
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