Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Galanos, Panagiotis; Pappas, George D.; Polyzos, Alexander; Kotsinas, Athanassios; Svolaki, Ioanna; Giakoumakis, Nickolaos Nikiforos; Glytsou, Christina; Pateras, Ioannis S.; Swain, Umakanta; Souliotis, Vassilis L.; Georgakilas, Alexandros G.; Geacintov, Nicholas E.; Scorrano, Luca; Lukas, Claudia; Lukáš, Jiří; Livneh, Zvi; Lygerou, Zoi; Chowdhury, Dipanjan; Sørensen, Claus Storgaard; Bártek, Jiří; Gorgoulis, Vassilis G.

doi:10.1186/s13059-018-1401-9

Cited by 64 publications

(57 citation statements)

References 82 publications

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“…In these cancer cells, DNA DSBs exist, but the DNA damage checkpoint pathway is compromised during cancer development, often by mutation/downregulation of checkpoint proteins [3,36,40]. Furthermore, inhibition of certain repair pathways would lead to a shift in repair mechanisms particularly to errorprone ones that facilitates genomic instability [41]. JMJD6 is upregulated in several types of cancer [42]; it is natural to speculate that JMJD6 overexpression-mediated inhibition of DNA repair may be one of the reasons for the increased genomic instability of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

JMJD6 modulates DNA damage response through downregulating H4K16ac independently of its enzymatic activity

et al. 2019

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The initiation and transduction of DNA damage response (DDR) occur in the context of chromatin, and modifications as well as the structure of chromatin are crucial for DDR signaling. How the profound chromatin alterations are confined to DNA lesions by epigenetic factors remains largely unclear. Here, we discover that JMJD6, a Jumonji C domain-containing protein, is recruited to DNA double-strand breaks (DSBs) after microirradiation. JMJD6 controls the spreading of histone ubiquitination, as well as the subsequent accumulation of repair proteins and transcriptional silencing around DSBs, but does not regulate the initial DNA damage sensing. Furthermore, JMJD6 deficiency results in promotion of the efficiency of nonhomologous end joining (NHEJ) and homologous recombination (HR), rapid cell-cycle checkpoint recovery, and enhanced survival after irradiation. Regarding the mechanism involved, we demonstrate that JMJD6, independently of its catalytic activity, interacts with SIRT1 and recruits it to chromatin to downregulate H4K16ac around DSBs. Our study reveals JMJD6 as a modulator of the epigenome around DNA lesions, and adds to the understanding of the role of epigenetic factors in DNA damage response. modifications and chromatin structure around DSBs play essential roles in DDR [4], and the degree and spreading distance of histone modifications around DSBs should be tightly monitored. For example, the spreading of γH2A.X and histone ubiquitination is both well controlled to insulate chromatin from DNA damage signaling [5-8]. However, how the epigenetic alterations are confined to the sites of DNA damage is still an outstanding conundrum, and needs to be further investigated. JMJD6, which contains a Jumonji C (JMJC) domain, functions as an iron-and α-oxoglutarate-dependent histone arginine demethylase [9, 10] or hydroxylase [11], regulating gene transcription and RNA splicing [10, 11]. Whether JMJD6 participates in genomic stability regulation, and whether its enzymatic activity is involved, need to be explored. We report here that JMJD6, independently of its catalytic activity, plays important roles in controlling DDR signaling in cells. Materials and methods Cells and reagents U2OS and MCF-7 cells were from ATCC (Manassas, VA, USA). Cells were cultured in Dulbecco's modified Eagle's Medium supplemented with 10% fetal bovine serum Edited by M. Oren

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Section: Discussionmentioning

confidence: 99%

JMJD6 modulates DNA damage response through downregulating H4K16ac independently of its enzymatic activity

et al. 2019

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“…One of the best studied examples is E2F1, for which both KO and overexpressing mice have been generated and both develop tumors . Similarly, chronic expression of p21 was recently shown to cause genomic instability in addition to its long‐standing role as a tumor suppressor.…”

Section: Resultsmentioning

confidence: 99%

Geminin ablation in vivo enhances tumorigenesis through increased genomic instability

Tsaniras

Villiou

Giannou

et al. 2018

The Journal of Pathology

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Geminin, a DNA replication licensing inhibitor, ensures faithful DNA replication in vertebrates. Several studies have shown that geminin depletion in vitro results in rereplication and DNA damage, whereas increased expression of geminin has been observed in human cancers. However, conditional inactivation of geminin during embryogenesis has not revealed any detectable DNA replication defects. In order to examine its role in vivo, we conditionally inactivated geminin in the murine colon and lung, and assessed chemically induced carcinogenesis. We show here that mice lacking geminin develop a significantly higher number of tumors and bear a larger tumor burden than sham-treated controls in urethane-induced lung and azoxymethane/dextran sodium sulfate-induced colon carcinogenesis. Survival is also significantly reduced in mice lacking geminin during lung carcinogenesis. A significant increase in the total number and grade of lesions (hyperplasias, adenomas, and carcinomas) was also confirmed by hematoxylin and eosin staining. Moreover, increased genomic aberrations, identified by increased ATR and γH2AX expression, was detected with immunohistochemistry analysis. In addition, we analyzed geminin expression in human colon cancer, and found increased expression, as well as a positive correlation with ATM/ATR levels and a non-monotonic association with γH2AX. Taken together, our data demonstrate that geminin acts as a tumor suppressor by safeguarding genome stability, whereas its overexpression is also associated with genomic instability. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Under these conditions, RAD52 has been shown to perform roles either downstream or upstream DSBs formation [45,82,102]. Several works in the last years supported or reported a function for RAD52 in the repair of collapsed replication forks by BIR [45,47,59,109,110]. In yeast, the relevance of Rad52 for BIR have been vastly demonstrated over the years as well as it has been shown that Rad52 participates to both Rad51-dependent and independent BIR [42].…”

Section: Rad52 As a Partner Of Mus81mentioning

confidence: 99%

“…Since all this would happen in a situation in which RAD51 cannot be assembled to protect the fork-i.e., BRCA2-deficiency-it makes sense that a D-loop assembled by RAD51 is refractory to MUS81-dependent cleavage [102]. Worth noting, RAD52 is required to ensure replication fork progression under these situations although its activation greatly stimulates rearrangements being able to produce specific mutational signatures as found also in yeast cells [42,109,[115][116][117][118].…”

Section: Rad52 As a Partner Of Mus81mentioning

confidence: 99%

“…RAD52 might be involved in repair of the resulting, MUS81-dependent, DSBs by BIR or, alternatively, by SSA. In both cases, this pathway could be highly mutagenic [109,110,118]. Hence, RAD52 might be highly relevant for the emergence of genome instability in tumors and its frequent overexpression in tumors could correlate with its crucial function to repair DSBs at replication forks after loss of p53, one of the most frequently-mutated oncosuppressor [109,132].…”

Section: Conclusion and Potential Implications Of Replication Fork-rmentioning

confidence: 99%

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Physiological and Pathological Roles of RAD52 at DNA Replication Forks

Malacaria

Honda

Franchitto

et al. 2020

Cancers

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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.Cancers 2020, 12, 402 2 of 17 for all known homology-directed DNA repair mechanisms in yeast [11,13,14], mammalian RAD52 was previously considered to be dispensable for recombination-based DNA repair and its knock out in mouse does not show any lethality or other remarkable phenotypes as those associated with the RAD51 knock out [15,16]. Based on the studies in chicken DT40 cells [16,17], it has been proposed that the vertebrate RAD52 may be involved only in a limited subset of the recombinational DNA repair events. Indeed, the most crucial recombination mediator function of yeast Rad52 is played by BRCA2 tumor suppressor protein in higher eukaryotes, including mammals, fungi, and plants [18][19][20].Remarkably, much interest in RAD52 function arose since its deficiency has been shown to be synthetic lethal with biallelic mutations in or absence of BRCA1/2 or BRCA-related genes [13,[21][22][23], which are found mutated or de-regulated in many hereditary and sporadic breast and ovarian cancers [24,25].While biochemical features of RAD52, its more novel double-strand break (DSB) repair functions and its modifications are the focus of other reviews in this issue [12,[26][27][28], here, we will discuss the unexpected roles that RAD52 plays at the DNA replication fork and their implications for cancer therapy. Role of RAD52 in DSBs Repair

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Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability

Cited by 64 publications

References 82 publications

JMJD6 modulates DNA damage response through downregulating H4K16ac independently of its enzymatic activity

JMJD6 modulates DNA damage response through downregulating H4K16ac independently of its enzymatic activity

Geminin ablation in vivo enhances tumorigenesis through increased genomic instability

Physiological and Pathological Roles of RAD52 at DNA Replication Forks

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