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Article ; Online: WRNIP1 prevents transcription-associated genomic instability.

Valenzisi, Pasquale / Marabitti, Veronica / Pichierri, Pietro / Franchitto, Annapaola

2024 Volume 12

Abstract: R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human ... ...

Abstract	R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified fork protection factors and DNA damage response proteins as regulators of R-loop dynamics. In this study, we identify the Werner helicase-interacting protein 1 (WRNIP1) as a novel factor that counteracts transcription-associated DNA damage upon replication perturbation. Loss of WRNIP1 leads to R-loop accumulation, resulting in collisions between the replisome and transcription machinery. We observe co-localization of WRNIP1 with transcription/replication complexes and R-loops after replication perturbation, suggesting its involvement in resolving transcription-replication conflicts. Moreover, WRNIP1-deficient cells show impaired replication restart from transcription-induced fork stalling. Notably, transcription inhibition and RNase H1 overexpression rescue all the defects caused by loss of WRNIP1. Importantly, our findings highlight the critical role of WRNIP1 ubiquitin-binding zinc finger (UBZ) domain in preventing pathological persistence of R-loops and limiting DNA damage, thereby safeguarding genome integrity.
MeSH term(s)	Humans ; ATPases Associated with Diverse Cellular Activities/metabolism ; DNA ; DNA Damage ; DNA Replication ; DNA-Binding Proteins/metabolism ; Genomic Instability ; Hydrolases/genetics ; Zinc Fingers
Chemical Substances	ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-) ; DNA (9007-49-2) ; DNA-Binding Proteins ; Hydrolases (EC 3.-) ; WRNIP1 protein, human (EC 3.6.1.3)
Language	English
Publishing date	2024-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.89981
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: RAD52 prevents accumulation of Polα-dependent replication gaps at perturbed replication forks in human cells.

Di Biagi, Ludovica / Malacaria, Eva / Aiello, Francesca Antonella / Valenzisi, Pasquale / Marozzi, Giorgia / Franchitto, Annapaola / Pichierri, Pietro

bioRxiv : the preprint server for biology

2023

Abstract: Replication gaps can arise as a consequence of perturbed DNA replication and their accumulation might undermine the stability of the genome. Loss of RAD52, a protein involved in the regulation of fork reversal, promotes accumulation of parental ssDNA ... ...

Abstract	Replication gaps can arise as a consequence of perturbed DNA replication and their accumulation might undermine the stability of the genome. Loss of RAD52, a protein involved in the regulation of fork reversal, promotes accumulation of parental ssDNA gaps during replication perturbation. Here, we demonstrate that this is due to the engagement of Polα downstream of the extensive degradation of perturbed replication forks after their reversal, and is not dependent on PrimPol. Polα is hyper-recruited at parental ssDNA in the absence of RAD52, and this recruitment is dependent on fork reversal enzymes and RAD51. Of note, we report that the interaction between Polα and RAD51 is stimulated by RAD52 inhibition, and Polα-dependent gap accumulation requires nucleation of RAD51 suggesting that it occurs downstream strand invasion. Altogether, our data indicate that RAD51-Polα-dependent repriming is essential to promote fork restart and limit DNA damage accumulation when RAD52 function is disabled.
Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.12.536536
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: R-Loop-Associated Genomic Instability and Implication of WRN and WRNIP1.

Marabitti, Veronica / Valenzisi, Pasquale / Lillo, Giorgia / Malacaria, Eva / Palermo, Valentina / Pichierri, Pietro / Franchitto, Annapaola

International journal of molecular sciences

2022 Volume 23, Issue 3

Abstract: Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, ... ...

Abstract	Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, a source of genomic instability and a notable hallmark of pre-cancerous and cancerous cells. Notably, one of the major natural threats for DNA replication is transcription. Encounters or conflicts between replication and transcription are unavoidable, as they compete for the same DNA template, so that collisions occur quite frequently. The main harmful transcription-associated structures are R-loops. These are DNA structures consisting of a DNA-RNA hybrid and a displaced single-stranded DNA, which play important physiological roles. However, if their homeostasis is altered, they become a potent source of replication stress and genome instability giving rise to several human diseases, including cancer. To combat the deleterious consequences of pathological R-loop persistence, cells have evolved multiple mechanisms, and an ever growing number of replication fork protection factors have been implicated in preventing/removing these harmful structures; however, many others are perhaps still unknown. In this review, we report the current knowledge on how aberrant R-loops affect genome integrity and how they are handled, and we discuss our recent findings on the role played by two fork protection factors, the Werner syndrome protein (WRN) and the Werner helicase-interacting protein 1 (WRNIP1) in response to R-loop-induced genome instability.
MeSH term(s)	ATPases Associated with Diverse Cellular Activities/metabolism ; DNA Replication ; DNA-Binding Proteins/metabolism ; Genomic Instability ; Humans ; R-Loop Structures ; Transcription, Genetic ; Werner Syndrome Helicase/metabolism
Chemical Substances	DNA-Binding Proteins ; WRNIP1 protein, human (EC 3.6.1.3) ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-) ; WRN protein, human (EC 3.6.4.12) ; Werner Syndrome Helicase (EC 3.6.4.12)
Language	English
Publishing date	2022-01-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23031547
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Phosphorylation status of MUS81 is a modifier of Olaparib sensitivity in BRCA2-deficient cells.

Blandino, Francesca / Malacaria, Eva / Figlioli, Carolina / Noto, Alessandro / Pugliese, Giusj Monia / Franchitto, Annapaola / Pichierri, Pietro

Nucleic acids research

2023 Volume 51, Issue 13, Page(s) 6723–6737

Abstract: The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different ... ...

Abstract	The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M- or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicate that deregulated action of the mitotic active form of MUS81 in S-phase leads to the cleavage of stalled replication forks before their reversal, bypassing fork deprotection, and engaging a Polθ-dependent DSBs repair. Collectively, our findings describe a novel mechanism leading to PARPi resistance that involves unscheduled MUS81-dependent cleavage of intact, unreversed replication forks. Since this cleavage occurs mimicking the phosphorylated status of S87 of MUS81, our data suggest that hyperphosphorylation of this residue in S-phase might represent a novel biomarker to identify resistance to PARPi.
MeSH term(s)	Animals ; DNA Replication ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Mammals/metabolism ; Phosphorylation ; Antineoplastic Agents/metabolism
Chemical Substances	DNA-Binding Proteins ; Endonucleases (EC 3.1.-) ; olaparib (WOH1JD9AR8) ; Antineoplastic Agents
Language	English
Publishing date	2023-05-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad470
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Article ; Online: Using a Human Papillomavirus Model to Study DNA Replication and Repair of Wild Type and Damaged DNA Templates in Mammalian Cells.

Das, Dipon / Bristol, Molly L / Pichierri, Pietro / Morgan, Iain M

International journal of molecular sciences

2020 Volume 21, Issue 20

Abstract: Human papillomaviruses have 8kbp DNA episomal genomes that replicate autonomously from host DNA. During initial infection, the virus increases its copy number to 20-50 copies per cell, causing torsional stress on the replicating DNA. This activates the ... ...

Abstract	Human papillomaviruses have 8kbp DNA episomal genomes that replicate autonomously from host DNA. During initial infection, the virus increases its copy number to 20-50 copies per cell, causing torsional stress on the replicating DNA. This activates the DNA damage response (DDR) and HPV replicates its genome, at least in part, using homologous recombination. An active DDR is on throughout the HPV life cycle. Two viral proteins are required for replication of the viral genome; E2 binds to 12bp palindromic sequences around the A/T rich origin of replication and recruits the viral helicase E1 via a protein-protein interaction. E1 forms a di-hexameric complex that replicates the viral genome in association with host factors. Transient replication assays following transfection with E1-E2 expression plasmids, along with an origin containing plasmid, allow monitoring of E1-E2 replication activity. Incorporating a bacterial lacZ gene into the origin plasmid allows for the determination of replication fidelity. Here we describe how we exploited this system to investigate replication and repair in mammalian cells, including using damaged DNA templates. We propose that this system has the potential to enhance the understanding of cellular components involved in DNA replication and repair.
MeSH term(s)	Alphapapillomavirus/genetics ; Alphapapillomavirus/metabolism ; Animals ; DNA Damage ; DNA Repair ; DNA Replication ; Genetic Engineering/methods ; Humans
Language	English
Publishing date	2020-10-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21207564
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Article: Physiological and Pathological Roles of RAD52 at DNA Replication Forks.

Malacaria, Eva / Honda, Masayoshi / Franchitto, Annapaola / Spies, Maria / Pichierri, Pietro

Cancers

2020 Volume 12, Issue 2

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 ... ...

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 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.
Language	English
Publishing date	2020-02-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12020402
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Article ; Online: R-Loop-Associated Genomic Instability and Implication of WRN and WRNIP1

Veronica Marabitti / Pasquale Valenzisi / Giorgia Lillo / Eva Malacaria / Valentina Palermo / Pietro Pichierri / Annapaola Franchitto

International Journal of Molecular Sciences, Vol 23, Iss 1547, p

2022 Volume 1547

Abstract	Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, a source of genomic instability and a notable hallmark of pre-cancerous and cancerous cells. Notably, one of the major natural threats for DNA replication is transcription. Encounters or conflicts between replication and transcription are unavoidable, as they compete for the same DNA template, so that collisions occur quite frequently. The main harmful transcription-associated structures are R-loops. These are DNA structures consisting of a DNA–RNA hybrid and a displaced single-stranded DNA, which play important physiological roles. However, if their homeostasis is altered, they become a potent source of replication stress and genome instability giving rise to several human diseases, including cancer. To combat the deleterious consequences of pathological R-loop persistence, cells have evolved multiple mechanisms, and an ever growing number of replication fork protection factors have been implicated in preventing/removing these harmful structures; however, many others are perhaps still unknown. In this review, we report the current knowledge on how aberrant R-loops affect genome integrity and how they are handled, and we discuss our recent findings on the role played by two fork protection factors, the Werner syndrome protein (WRN) and the Werner helicase-interacting protein 1 (WRNIP1) in response to R-loop-induced genome instability.
Keywords	genomic instability ; replication stress ; DNA repair ; RecQ helicases ; R-loops ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Human RAD52 double-ring remodels replication forks restricting fork reversal.

Honda, Masayoshi / Razzaghi, Mortezaali / Gaur, Paras / Malacaria, Eva / Di Biagi, Ludovica / Aiello, Francesca Antonella / Paintsil, Emeleeta A / Stanfield, Andrew / Deppe, Bailey J / Gakhar, Lokesh / Schnicker, Nicholas J / Spies, M Ashley / Pichierri, Pietro / Spies, Maria

bioRxiv : the preprint server for biology

2023

Abstract: ... Human ... ...

Abstract	Human RAD52
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.14.566657
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: PHOSPHORYLATION-DEPENDENT ASSOCIATION OF WRN WITH RPA IS REQUIRED FOR RECOVERY OF REPLICATION FORKS STALLED AT SECONDARY DNA STRUCTURES.

Noto, Alessandro / Valenzisi, Pasquale / Fratini, Federica / Kulikowicz, Tomasz / Sommers, Joshua A / Di Feo, Flavia / Palermo, Valentina / Semproni, Maurizio / Crescenzi, Marco / Brosh, Robert M / Franchitto, Annapaola / Pichierri, Pietro

bioRxiv : the preprint server for biology

2023

Abstract: The WRN protein mutated in the hereditary premature aging disorder Werner syndrome plays a vital role in handling, processing, and restoring perturbed replication forks. One of its most abundant partners, Replication Protein A (RPA), has been shown to ... ...

Abstract	The WRN protein mutated in the hereditary premature aging disorder Werner syndrome plays a vital role in handling, processing, and restoring perturbed replication forks. One of its most abundant partners, Replication Protein A (RPA), has been shown to robustly enhance WRN helicase activity in specific cases when tested
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.08.552428
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Article ; Online: Therapeutic disruption of RAD52-ssDNA complexation via novel drug-like inhibitors.

Bhat, Divya S / Malacaria, Eva / Biagi, Ludovica Di / Razzaghi, Mortezaali / Honda, Masayoshi / Hobbs, Kathryn F / Hengel, Sarah R / Pichierri, Pietro / Spies, M Ashley / Spies, Maria

NAR cancer

2023 Volume 5, Issue 2, Page(s) zcad018

Abstract: RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ... ...

Abstract	RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52-ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches. Using pharmacophoric informatics on the RAD52 complexation by epigallocatechin (EGC), and the Enamine
Language	English
Publishing date	2023-05-01
Publishing country	England
Document type	Journal Article
ISSN	2632-8674
ISSN (online)	2632-8674
DOI	10.1093/narcan/zcad018
Database	MEDical Literature Analysis and Retrieval System OnLINE

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