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Cancers
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Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights
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Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 September 2019) | Viewed by 32347

Special Issue Editors

Prof. Dr. Lisa Wiesmüller

E-Mail Website
Guest Editor
Division of Gynecological Oncology, Department of Obstetrics and Gynecology of the University of Ulm, Prittwitzstrasse 43, 89075 Ulm, Germany
Interests: DNA repair; recombination and replication; DNA damage response (DDR); DNA tolerance mechanisms; biomarkers and therapeutic strategies targeting DDR factors
Dr. Vanesa Gottifredi

E-Mail Website
Guest Editor
Fundación Instituto Leloir. Av. Patricias Argentinas 435, 1425 Buenos Aires. Argentina
Interests: DNA repair, recombination and replication, DNA damage response (DDR), DNA tolerance mechanisms, biomarkers and therapeutic strategies targeting DDR factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

In this Special Issue we would like to zoom into the different functions of the RAD52 helicase-like protein and the current implications of such findings for cancer treatment. Over the last few years, different laboratories have discovered particular activities of mammalian RAD52 both in the S- and M-phase that are distinct from the auxiliary role of yeast rad52 in homologous recombination. At DNA double-strand breaks, RAD52 was demonstrated to spur alternative pathways in compensating for loss of homologous recombination functions. At collapsed replication forks RAD52 activates break-induced replication. In the M-phase, RAD52 promotes the finalization of DNA replication. Its compensatory role in the resolution of DNA double-strand breaks has put RAD52 in the focus of synthetic lethal strategies, which is particularly relevant for cancer treatment.

In this Special Issue, we will gather experts in the field to convey comprehensive, insightful and current perspectives on the role of RAD52 in the maintenance of genomic integrity.

Prof. Dr. Lisa Wiesmüller
Dr. Vanesa Gottifredi
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. Cancers 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 2900 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

  • homologous recombination
  • alternative end joining
  • break-induced replication
  • common fragile sites
  • mitotic DNA synthesis
  • synthetic lethality

Published Papers (7 papers)

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Editorial

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8 pages, 580 KiB  
Editorial
Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights
by Vanesa Gottifredi and Lisa Wiesmüller
Cancers 2020, 12(3), 705; https://doi.org/10.3390/cancers12030705 - 17 Mar 2020
Cited by 5 | Viewed by 3419
Abstract
In this Special Issue, we would like to focus on the various functions of the RAD52 helicase-like protein and the current implications of such findings for cancer treatment. Over the last few years, various laboratories have discovered particular activities of mammalian RAD52—both in [...] Read more.
In this Special Issue, we would like to focus on the various functions of the RAD52 helicase-like protein and the current implications of such findings for cancer treatment. Over the last few years, various laboratories have discovered particular activities of mammalian RAD52—both in S and M phase—that are distinct from the auxiliary role of yeast RAD52 in homologous recombination. At DNA double-strand breaks, RAD52 was demonstrated to spur alternative pathways to compensate for the loss of homologous recombination functions. At collapsed replication forks, RAD52 activates break-induced replication. In the M phase, RAD52 promotes the finalization of DNA replication. Its compensatory role in the resolution of DNA double-strand breaks has put RAD52 in the focus of synthetic lethal strategies, which is particularly relevant for cancer treatment. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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Review

Jump to: Editorial

17 pages, 1069 KiB  
Review
Physiological and Pathological Roles of RAD52 at DNA Replication Forks
by Eva Malacaria, Masayoshi Honda, Annapaola Franchitto, Maria Spies and Pietro Pichierri
Cancers 2020, 12(2), 402; https://doi.org/10.3390/cancers12020402 - 10 Feb 2020
Cited by 15 | Viewed by 4829
Abstract
Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It [...] Read more.
Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It is also an Achille’s heel of cancer. Thus, identification of pathways used by the cancer cells to respond to replication-stress may assist in the identification of new biomarkers and discovery of new therapeutic targets. Alternative mechanisms that act at perturbed DNA replication forks and involve fork degradation by nucleases emerged as crucial for sensitivity of cancer cells to chemotherapeutics agents inducing replication stress. Despite its important role in homologous recombination and recombinational repair of DNA double strand breaks in lower eukaryotes, RAD52 protein has been considered dispensable in human cells and the full range of its cellular functions remained unclear. Very recently, however, human RAD52 emerged as an important player in multiple aspects of replication fork metabolism under physiological and pathological conditions. In this review, we describe recent advances on RAD52’s key functions at stalled or collapsed DNA replication forks, in particular, the unexpected role of RAD52 as a gatekeeper, which prevents unscheduled processing of DNA. Last, we will discuss how these functions can be exploited using specific inhibitors in targeted therapy or for an informed therapy selection. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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11 pages, 825 KiB  
Review
RAD52: Viral Friend or Foe?
by Eric A. Hendrickson
Cancers 2020, 12(2), 399; https://doi.org/10.3390/cancers12020399 - 08 Feb 2020
Cited by 9 | Viewed by 2779
Abstract
Mammalian Radiation Sensitive 52 (RAD52) is a gene whose scientific reputation has recently seen a strong resurgence. In the past decade, RAD52, which was thought to be dispensable for most DNA repair and recombination reactions in mammals, has been shown to [...] Read more.
Mammalian Radiation Sensitive 52 (RAD52) is a gene whose scientific reputation has recently seen a strong resurgence. In the past decade, RAD52, which was thought to be dispensable for most DNA repair and recombination reactions in mammals, has been shown to be important for a bevy of DNA metabolic pathways. One of these processes is termed break-induced replication (BIR), a mechanism that can be used to re-start broken replication forks and to elongate the ends of chromosomes in telomerase-negative cells. Viruses have historically evolved a myriad of mechanisms in which they either conscript cellular factors or, more frequently, inactivate them as a means to enable their own replication and survival. Recent data suggests that Adeno-Associated Virus (AAV) may replicate its DNA in a BIR-like fashion and/or utilize RAD52 to facilitate viral transduction and, as such, likely conscripts/requires the host RAD52 protein to promote its perpetuation. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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11 pages, 1196 KiB  
Review
When RAD52 Allows Mitosis to Accept Unscheduled DNA Synthesis
by Camille Franchet and Jean-Sébastien Hoffmann
Cancers 2020, 12(1), 26; https://doi.org/10.3390/cancers12010026 - 19 Dec 2019
Cited by 17 | Viewed by 4022
Abstract
Faithful duplication of the human genome during the S phase of cell cycle and accurate segregation of sister chromatids in mitosis are essential for the maintenance of chromosome stability from one generation of cells to the next. Cells that are copying their DNA [...] Read more.
Faithful duplication of the human genome during the S phase of cell cycle and accurate segregation of sister chromatids in mitosis are essential for the maintenance of chromosome stability from one generation of cells to the next. Cells that are copying their DNA in preparation for division can suffer from ‘replication stress’ (RS) due to various external or endogenous impediments that slow or stall replication forks. RS is a major cause of pathologies including cancer, premature ageing and other disorders associated with genomic instability. It particularly affects genomic loci where progression of replication forks is intrinsically slow or problematic, such as common fragile site (CFS), telomeres, and repetitive sequences. Although the eukaryotic cell cycle is conventionally thought of as several separate steps, each of which must be completed before the next one is initiated, it is now accepted that incompletely replicated chromosomal domains generated in S phase upon RS at these genomic loci can result in late DNA synthesis in G2/M. In 2013, during investigations into the mechanism by which the specialized DNA polymerase eta (Pol η) contributes to the replication and stability of CFS, we unveiled that indeed some DNA synthesis was still occurring in early mitosis at these loci. This surprising observation of mitotic DNA synthesis that differs fundamentally from canonical semi-conservative DNA replication in S-phase has been then confirmed, called “MiDAS”and believed to counteract potentially lethal chromosome mis-segregation and non-disjunction. While other contributions in this Special Issue of Cancers focus on the role of RAS52RAD52 during MiDAS, this review emphases on the discovery of MiDAS and its molecular effectors. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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16 pages, 1835 KiB  
Review
RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies
by Monika Toma, Katherine Sullivan-Reed, Tomasz Śliwiński and Tomasz Skorski
Cancers 2019, 11(10), 1561; https://doi.org/10.3390/cancers11101561 - 14 Oct 2019
Cited by 33 | Viewed by 5901
Abstract
Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting [...] Read more.
Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2—mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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13 pages, 1041 KiB  
Review
Replication Stress Response Links RAD52 to Protecting Common Fragile Sites
by Xiaohua Wu
Cancers 2019, 11(10), 1467; https://doi.org/10.3390/cancers11101467 - 29 Sep 2019
Cited by 14 | Viewed by 3652
Abstract
Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged [...] Read more.
Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged with the discovery of its important backup role to BRCA (breast cancer genes) in HR. Recent new evidence further demonstrates that RAD52 possesses multiple activities to cope with replication stress. For example, replication stress-induced DNA repair synthesis in mitosis (MiDAS) and oncogene overexpression-induced DNA replication are dependent on RAD52. RAD52 becomes essential in HR to repair DSBs containing secondary structures, which often arise at collapsed replication forks. RAD52 is also implicated in break-induced replication (BIR) and is found to inhibit excessive fork reversal at stalled replication forks. These various functions of RAD52 to deal with replication stress have been linked to the protection of genome stability at common fragile sites, which are often associated with the DNA breakpoints in cancer. Therefore, RAD52 has important recombination roles under special stress conditions in mammalian cells, and presents as a promising anti-cancer therapy target. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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13 pages, 634 KiB  
Review
Emerging Roles of RAD52 in Genome Maintenance
by Manisha Jalan, Kyrie S. Olsen and Simon N. Powell
Cancers 2019, 11(7), 1038; https://doi.org/10.3390/cancers11071038 - 23 Jul 2019
Cited by 41 | Viewed by 7106
Abstract
The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, [...] Read more.
The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, especially in HR-deficient cells. One of the factors that appears to have a role in many of these pathways is human RAD52, a DNA repair protein that was previously considered to be dispensable due to a lack of an observable phenotype in knock-out mice. In later studies, RAD52 deficiency has been shown to be synthetically lethal with defects in BRCA genes, making RAD52 an attractive therapeutic target, particularly in the context of BRCA-deficient tumors. Full article
(This article belongs to the Special Issue Current Understanding of RAD52 Functions: Fundamental and Therapeutic Insights)
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