E2F transcription factors and their complementary roles during DNA damage responses

生物 抑制因子 E2F型 转录因子 细胞周期 抄写(语言学) 细胞分裂 拟南芥 遗传学 DNA结合蛋白 细胞生长 视网膜母细胞瘤蛋白 细胞命运测定 细胞周期蛋白 细胞生物学 细胞 基因 突变体 哲学 语言学
作者
Paula Casati
出处
期刊:Molecular Plant [Elsevier]
卷期号:16 (9): 1373-1375
标识
DOI:10.1016/j.molp.2023.08.008
摘要

E2F transcription factors (TF) comprise a family of proteins that regulate the expression of genes required for S-phase progression, among others. Arabidopsis genome encodes six E2F TFs (E2FA–F), which are classified as typical (E2FA–C) and atypical (E2FD–F) depending on their ability to interact with two DP interaction proteins (DPa and DPb) (Sablowski and Gutierrez, 2022Sablowski R. Gutierrez C. Cycling in a crowd: Coordination of plant cell division, growth, and cell fate.Plant Cell. 2022; 34: 193-208Crossref PubMed Scopus (22) Google Scholar). While E2FA–C need to heterodimerize with either DPa or DPb to function, E2FD–F act independently of DP proteins. Moreover, the retinoblastoma-related1 (RBR1) protein also binds and inhibits the typical E2F/DP TF complexes when bound to the promoter of genes, repressing their expression in the absence of a signal to enter a new cell cycle. In general, E2FA and E2FB are considered transcriptional activators, while E2FC is generally considered a repressor of cell proliferation (Sablowski and Gutierrez, 2022Sablowski R. Gutierrez C. Cycling in a crowd: Coordination of plant cell division, growth, and cell fate.Plant Cell. 2022; 34: 193-208Crossref PubMed Scopus (22) Google Scholar). In addition, it is well documented that E2FB at least, and probably E2FA, can also stimulate the G2/M transition. Besides regulating cell-cycle progression, E2F TFs also have other roles, for example during the DNA damage response, which is activated by various genotoxic conditions; in particular, different studies have demonstrated that E2FA, E2FB, and RBR1 all play a role in the DNA damage response (DDR) response in plants (Biedermann et al., 2017Biedermann S. Harashima H. Chen P. Heese M. Bouyer D. Sofroni K. Schnittger A. The retinoblastoma homolog RBR1 mediates localization of the repair protein RAD51 to DNA lesions in Arabidopsis.EMBO J. 2017; 36: 1279-1297Crossref PubMed Scopus (54) Google Scholar; Horvath et al., 2017Horvath B.M. Kourova H. Nagy S. Nemeth E. Magyar Z. Papdi C. Ahmad Z. Sanchez-Perez G.F. Perilli S. Blilou I. et al.Arabidopsis RETINOBLASTOMA 746 RELATED directly regulates DNA damage responses through functions beyond cell cycle control.EMBO J. 2017; 36: 1261-1278Crossref PubMed Scopus (67) Google Scholar; Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar; Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar; Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). E2FA and E2FB were previously thought to be partially redundant; however, recent reports have shown that differences exist between E2FA and E2FB. In a recent study by Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, the authors demonstrated that E2FA and E2FB have different and non-redundant roles during replication stress. First, they showed that E2FA and E2FB share many target genes with the central DDR transcriptional regulator SUPPRESSOR OF GAMMA-RESPONSE 1 (SOG1). Next, they compared the position of E2F TF binding sites with those previously identified for SOG1 (Bourbousse et al., 2018Bourbousse C. Vegesna N. Law J.A. SOG1 activator and MYB3R 699 repressors regulate a complex DNA damage network in Arabidopsis.Proc. Natl. Acad. Sci. USA. 2018; 115E12453Crossref PubMed Scopus (77) Google Scholar), showing that both E2FA and E2FB could bind to common target genes at positions close to the SOG1-binding site. These results suggest that E2FA/B can activate target genes important during the DDR (Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Interestingly, E2FA/B also regulate SOG1 transcript levels, not only in plants under genotoxic stress conditions such as UV-B exposure but also under no-stress conditions (Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar), while SOG1 also increases E2FA expression (Mahapatra and Roy, 2021Mahapatra K. Roy S. SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis.Sci. Rep. 2021; 1111659Crossref PubMed Scopus (11) Google Scholar). Thus, E2FA/B not only regulate a subset of SOG1 target genes, therefore independently regulating genes of the DDR from this TF, but expression levels of all three genes are mutually coordinated (Figure 1). Despite both E2FA and E2FB being demonstrated to play a role during the DDR activated by different genotoxic agents, these reported roles seem to be different. For example, using plants under constitutive replication stress because they are hypomorphic mutants for DNA polymerase ε (pol2a), Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar generated double- and triple-mutant combinations between pol2a, sog1, and e2fa or e2fb mutants. Analysis of these mutant combinations showed that E2FB plays the most important role in maintaining plant growth under conditions of replicative stress, with E2A only having a minor role. Interestingly, a deficiency in the expression of e2fb affected both the rosette and the root size in plants under replication stress (Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar; Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In contrast, after a UV-B exposure that produces cyclobutane pyrimidine dimers and 6-4 photoproducts in the DNA, a deficiency of both E2Fa and E2Fb affected leaf size, while in the roots, E2FA, but not E2FB, regulated primary root elongation, cell proliferation, and programmed cell death in the meristematic zone (Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar). Moreover, the root phenotype after UV-B exposure observed in the e2fa mutant could not be reversed by overexpression with E2FB. Thus, E2FA and E2FB have different roles under different genotoxic stress conditions, and these roles are also different and non-redundant. In addition, Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar analyzed the role of E2FA and E2Fb in the primary root meristem of plants under replicative stress triggered by Pol ε. Results show that all seedlings under replicative stress have decreased root meristem size; however, root meristem length was further reduced in ef2b-1 pol2a and e2fb-1 pol2a sog1 mutants, while this effect was not observed in e2fa-1 pol2a and e2fa-1 pol2a sog1 mutants. These results demonstrate that E2FB, but not E2FA, plays a crucial role in proliferating cells, protecting them from cell proliferation arrest triggered by replication stress. In contrast, after UV-B exposure, e2fa, but not e2fb, mutants showed altered inhibition of cell proliferation in the primary root meristems (Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar), further validating the different roles of E2FA and E2FB under different genotoxic stress conditions. E2FB, together with E2FC and RBR1, is part of DREAM (DP, Rb-like, E2F, and MuvB) complexes, which are essential for the timely progression of transcriptional waves involved in cell-cycle regulation and cell differentiation (Magyar et al., 2016Magyar Z. Bögre L. Ito M. DREAMs make plant cells to cycle or to become quiescent.Curr. Opin. Plant Biol. 2016; 34: 100-106Crossref PubMed Scopus (38) Google Scholar; Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar). On the other hand, E2FA does not seen to be part of DREAM complexes in plants, despite it being able to interact with some components of these complexes, suggesting that E2FA association to DREAM complexes is weaker than E2FB interaction (Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar). This different association may account, at least in part, for the diverse responses reported. The specific role of E2FB during the response to other DNA-damaging agents has been also analyzed. Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar studied the participation of E2FB during DNA damage using cisplatin, which crosslinks DNA in several different ways, interfering with replication and cell division. In these experiments, e2fb mutants of different allelic strengths, e2fb-1 and e2fb-2, were used. Interestingly, the two mutant alleles showed a differential response to DNA damage, with the e2fb-2, but not the e2fb-1, mutant showing a significantly longer root than wild-type seedlings after transfer onto 15 μM cisplatin plates (Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar). The two e2fb alleles have been shown to differ in phenotypic strength, such as embryo size and seed maturation; this could be related to the site of T-DNA insertion, resulting in the inclusion (e2fb-1) or exclusion (e2fb-2) of the dimerization domain within the truncated E2FB protein (Leviczky et al., 2019Leviczky T. Molnár E. Papdi C. Őszi E. Horváth G.V. Vizler C. Nagy V. Pauk J. Bögre L. Magyar Z. E2FA and E2FB transcription factors coordinate cell proliferationwith seed maturation.Development. 2019; 146: dev179333Crossref PubMed Scopus (18) Google Scholar). On the other hand, the lower decrease in primary root elongation observed in e2fb mutants after cisplatin treatment contrasts the higher inhibition of primary root elongation measured in double ef2b-1 pol2a seedlings reported by Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar. In addition, when the same analysis was done using hydroxyurea (HU), which triggers replication stress by depleting the intracellular dNTP pool, neither e2fa nor e2fb mutants showed differences in primary root elongation compared to wild-type seedlings (Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). The diverse responses observed in these experiments may be because the different genotoxic agents used to impair replication may do so in distinct ways. For instance, in the experiments presented in Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, HU probably induces more moderate developmental defects than the pol2a mutation, as it may only affect the roots in direct contact with the genotoxic agent. In addition, or alternatively, in experiments done using external DNA damage agents such as cisplatin, HU, or UV-B (Lang et al., 2021Lang L. Pettkó-Szandtner A. Tunçay Elbaşı H. Takatsuka H. Nomoto Y. Zaki A. Dorokhov S. De Jaeger G. Eeckhout D. Ito M. et al.The DREAM complex represses growth in response to DNA damage in Arabidopsis.Life Sci. Alliance. 2021; 4e202101141Crossref Scopus (13) Google Scholar; Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar; Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar), plants were exposed to the genotoxic agent for a short period of time, in contrast to experiments done using pol2a mutants, which are constantly under replication stress. Despite the fact that E2FB has a major role during replicative stress, Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar showed that E2FA can also contribute to the replication stress response when E2FB is not expressed. The results presented demonstrate that e2fb-1 sog1, but not e2fa-1 sog1, mutants were more sensitive to HU than sog1 mutants. However, the e2fa-2 e2fb-1 sog1 triple mutant showed stronger hypersensitivity to HU than the double e2fb-1 sog1 mutant. Interestingly, E2FB overexpression cannot complement a mutation in E2FA during DDRs by UV-B in Arabidopsis roots, as e2fa mutants that overexpress E2Fb cannot revert the differential phenotypes reported under conditions of DNA damage (Gómez et al., 2022Gómez M.S. Sheridan M.L. Casati P. E2Fb and E2Fa transcription factors independently regulate the DNA damage response after ultraviolet B exposure in Arabidopsis.Plant J. 2022; 109: 1098-1115Crossref PubMed Scopus (5) Google Scholar). These differences further validate the differential pathways that can be activated by diverse conditions that produce genotoxic stress in plants. To summarize, different studies have reported the distinctive roles of E2FA and E2FB during DDRs, some of them independently of SOG1. However, their participation in these responses has been demonstrated to be distinct depending on the source of DNA damage or the replicative stressor. The results presented in Nisa et al., 2023Nisa M. Eekhout T. Bergis C. Pedroza-Garcia J.A. He X. Mazubert C. Vercauteren I. Cools T. Brik-Chaouche R. Drouin-Wahbi J. et al.Distinctive and complementary roles of E2F transcription factors during plant replication stress responses.Mol. Plant. 2023; 16: 1269-1282https://doi.org/10.1016/j.molp.2023.07.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar bring novel insights into the roles of these TFs in Arabidopsis plants and raise new questions about how the different response pathways in which E2FA and/or E2FB participate are regulated. We apologize to colleagues whose works are not cited due to space limitations. P.C. is funded by FONCyT grant 2019-167. P.C. is a member of the Researcher Career of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and a professor at UNR.
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