Editorial: Regulation and coordination of the different DNA damage responses and their role in tissue homeostasis maintenance

Edi o ial: Regula ion and coo dina ion o he di e en DNA damage esponses and hei ole in issue homeos asis main enance Luis Albe o Baena-López 1 *, An onio Baonza 2 *, Ca los Es ella 2 * and Héc o He anz 3 * 1 Si William Dunn School o Pa hology, Uni e si y o Ox o d, Ox o d, Uni ed Kingdom, 2 Cen o de Biología Molecula “Se e o Ochoa”, CSIC-UAM, Mad id, Spain, 3 Depa men o Cellula and Molecula Medicine, Uni e si y o Copenhagen, Copenhagen, Denma k KEYWORDS DNA damage, apop osis, cell p oli e a ion, issue homeos asis, DNA damage esponse Edi o ial on he Resea ch Topic Regula ion and coo dina ion o he di e en DNA damage esponses and hei ole in issue homeos asis main enance Cells a e cons an ly exposed o mul iple in e nal and ex e nal s esso s ha can damage hei gene ic ma e ial. To main ain genome s abili y and in eg i y, cells ha e e ol ed sophis ica ed molecula DNA damage esponse pa hways (DDRs), ha de ec and epai DNA lesions. The ac i a ion o hese pa hways igge s a wide ange o cellula esponses, including cell cycle a es , DNA epai , senescence, and apop osis, which p e en he p oli e a ion o cells wi h po en ially ha m ul DNA changes. Depending on he cell ype, s age o de elopmen , and p oli e a ion s a us, hese “li e” s. “dea h”decisions can di e . Apop osis, in pa icula , is o special in e es as de ec s in i s induc ion can con ibu e o umo igenesis o he esis ance o cance cells o he apeu ic agen s such as adio he apy. Al hough much p og ess has been made in ou comp ehension o he ac o s ha o m he DDR pa hways and hei ac i a ion, much emains o be in es iga ed on he coo dina ion and in eg a ion o hei induced se o cellula esponses. Add essing hese undamen al biological ques ions is c ucial o ully unde s and he molecula basis main aining issue homeos asis upon DNA damage as well as p e en ing he o ma ion o umou s. This special issue was en isioned o p o ide new insigh s ega ding his opic while illus a ing some o he complexi ies o he field. The Resea ch Topic includes se e al li e a u e e iews, as well as wo o iginal a icles ha p esen new findings. We hope ha hese a icles con ibu e o pic u e ou cu en unde s anding abou how he DDR coo dina es he induc ion o nume ous cellula e en s while s imula ing new lines o u u e esea ch in his impo an a ea o biology. In acellula and ex acellula signals can modula e nume ous cellula e en s a e DNA damage. Fo example, he No ch pa hway, which is in ol ed in a a ie y o de elopmen al and physiological p ocesses, can egula e he apop o ic esponse in cells showing lesions on hei DNA. The No ch ecep o nega i ely egula es he DDR by a enua ing he ac i i y o OPEN ACCESS EDITED AND REVIEWED BY You-Wen He, Duke Uni e si y, Uni ed S a es *CORRESPONDENCE Luis Albe o Baena-López, [email p o ec ed].ac.uk An onio Baonza, [email p o ec ed] Ca los Es ella, [email p o ec ed] Héc o He anz, [email p o ec ed] SPECIALTY SECTION This a icle was submi ed o Cell Dea h and Su i al, a sec ion o he jou nal F on ie s in Cell and De elopmen al Biology RECEIVED 27 Feb ua y 2023 ACCEPTED 02 Ma ch 2023 PUBLISHED 13 Ma ch 2023 CITATION Baena-López LA, Baonza A, Es ella C and He anz H (2023), Edi o ial: Regula ion and coo dina ion o he di e en DNA damage esponses and hei ole in issue homeos asis main enance. F on . Cell De . Biol. 11:1175155. doi: 10.3389/ cell.2023.1175155 COPYRIGHT © 2023 Baena-López, Baonza, Es ella and He anz. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Cell and De elopmen al Biology on ie sin.o g01 TYPE Edi o ial PUBLISHED 13 Ma ch 2023 DOI 10.3389/ cell.2023.1175155 he phospha idylinosi ol-3-like p o ein kinase a axia- elengiec asia mu a ed (ATM) (Ve mezo ic e al., 2015). In his way, No ch1 inhibi ion inc eases ATM-dependen apop osis in esponse o DNA damage. In a new s udy conduc ed by Nee u Saini and colleagues, hey explo e he ole o he nucleola localiza ion o he No ch1 in acellula domain (NIC1) du ing he induced apop o ic esponse by DNA damage (Saini e al., 2022). They specifically disco e ed ha NIC1 can in e ac wi h a molecula cascade in he nucleolus o p e en DNA damage- dependen apop osis. Th ough a ge ed gene ic mu a ions, hey also show ha he subcellula localiza ion o NIC1 in he nucleolus is egula ed by a p o ein called Si uin1. These findings, along wi h p e ious esea ch om he same labo a o y, shed new ligh on he ole o No ch signalling in egula ing he cellula esponse o DNA damage (Saini and Sa in, 2020). The p o eins in ol ed in he cell cycle con ol egula e he p ecise duplica ion and p opaga ion o genomes. De egula ion o cell cycle can a ec genome s abili y and consequen ly issue g ow h. Cyclins a e key cell cycle egula o s ha imely ac i a e cyclin- dependen kinases a di e en s ages o he cell cycle. Cyclin E p omo es G1-S p og ession in p oli e a ing cells. Cyclin E up egula ion abo e physiological le els can esul in eplica ion s ess and genomic ins abili y (Fagundes and Teixei a, 2021). No su p isingly, Cyclin E is commonly amplified in human cance s (Mache e and Halazone is, 2015). Al hough he oles o Cyclin E in no mal p oli e a ing cells ha e been ex ensi ely s udied, he implica ions o Cyclin E de egula ion in non-p oli e a ing issues emain poo ly unde s ood. In a s udy p esen ed in his Resea ch Topic, Molano-Fe nández and colleagues use he accesso y gland o D osophila as an in i o model o s udy he consequences o Cyclin E up egula ion in non-p oli e a ing cells (Molano-Fe nández e al., 2023). The accesso y gland o he ui fly is he unc ional o hologue o he human p os a e and is eme ging as a use ul pla o m o model di e en aspec s ela ed o p os a e cance (Rambu e al., 2021). Molano-Fe nández and colleagues show ha Cyclin E induces a iable le els o endo eplica ion, a singula ype o cycle in which cells go h ough ounds o DNA eplica ion in he absence o cell di ision. A di ec consequence o endo eplica ion is an inc eased cellula ploidy. Cyclin E-induced endo eplica ion in he accesso y gland is associa ed wi h ex ensi e DNA damage and de ec s in size and cellula o ganiza ion. The ac i a ion o he DDR commonly induces cell p oli e a ion a es and apop osis. Howe e , hese cellula ou comes a y depending on cell ype and con ex and can impac no only cell su i al bu also he e ficacy o he apeu ic s a egies o di e en diseases, including cance . Fo example, ionizing adia ion is pa icula ly e ec i e in a ge ing p oli e a i e cells (Ruiz-Losada e al., 2022). In he con ex o adia ion-induced DNA damage, Baonza and colleagues desc ibe he cascade o cellula esponses igge ed by his ype o damage in se e al D osophila issues and hei in e play wi h he apop osis machine y. The au ho s also explo e hypo he ical in insic mechanisms ha could mi iga e he apop o ic pa hway in esponse o adia ion-induced DNA damage, and how hese mechanisms could impac he esponsi eness o ans o med cells o adia ion he apy (Baonza e al., 2022). The ac i a ion o apop osis upon DNA damage seems o coo dina e no only he elimina ion o de ec i e cells bu also he egene a ion esponse in heal hy su ounding cells. This coo dina ion is c ucial o main ain issue homeos asis. Se as p o ides an in e es ing e iew desc ibing he po en ial unc ion o he MAP3 kinase Ask1 as a signaling coo dina o o bo h cell dea h and egene a ion induced by DDR (Se as, 2022). He desc ibes how cells wi h DNA damage p oduce la ge amoun s o eac i e oxygen species (ROS), which can ac i a e Ask1, JNK- signalling and ul ima ely lead o apop osis. This p ocess elimina es damaged cells and could seemingly coo dina e he egene a i e esponse in heal hy su ounding cells. In his ega d, he au ho hypo hesise ha a wa e o ROS om apop o ic cells and a mode a e ac i a ion o Ask1 in heal hy cells can acili a e he egene a i e p ocess. This opens new a enues o u u e esea ch in he egene a ion field. The beha iou o cells in bo h de elopmen al and pa hological con ex s is de e mined by hei unique gene exp ession p ofile. While changes in DNA sequence caused by mu agenic agen s is i e e sible, epigene ic modifica ions can e e sibly a ec gene exp ession. DNA me hyla ion, pa icula ly in CpG-en iched sequences, was he fi s ecognized epigene ic modifica ion, bu ecen esea ch has e ealed ha he me hyla ion s a us o a ious RNA ypes also significan ly a ec s hei s uc u al and unc ional cha ac e is ics. In hei li e a u e e iew, Alagia and Gulle o a p o ide a comp ehensi e o e iew o ou cu en knowledge ega ding he molecula ac o s con ibu ing o epigene ic egula ion ia RNA me hyla ion. They also desc ibe how inno a i e echniques a e acili a ing he s udy o hese c ucial modifica ions, and ul ima ely he physiological and pa hological implica ions, mainly in umou s, o hese epigene ic changes (Alagia and Gulle o a, 2022). Al hough many aspec s o he me hyla ion and deme hyla ion p ocess ha e been elucida ed in ecen yea s, he manusc ip iden ifies se e al c i ical ques ions ha emain un esol ed. Add essing hese ques ions could pa e he way o de eloping a ge ed he apies wi h significan clinical implica ions. Au ho con ibu ions LB-L, CE, HH, and AB w o e sec ions o he manusc ip . All au ho s ead and app o ed he submi ed e sion. Conflic o in e es The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o financial ela ionships ha could be cons ued as a po en ial conflic o in e es . Publishe ’s no e All claims exp essed in his a icle a e solely hose o he au ho s and do no necessa ily ep esen hose o hei a filia ed o ganiza ions, o hose o he publishe , he edi o s and he e iewe s. Any p oduc ha may be e alua ed in his a icle, o claim ha may be made by i s manu ac u e , is no gua an eed o endo sed by he publishe . F on ie s in Cell and De elopmen al Biology on ie sin.o g02 Baena-López e al. 10.3389/ cell.2023.1175155 Re e ences Alagia, A., and Gulle o a, M. (2022). The me hyla ion game: Epigene ic and epi ansc ip omic dynamics o 5-me hylcy osine. F on . Cell De . Biol. 10, 915685. doi:10.3389/ cell.2022.915685 Baonza, A., Tu -G acia, S., Pé ez-Aguile a, M., and Es ella, C. (2022). Regula ion and coo dina ion o he di e en DNA damage esponses in D osophila. F on . Cell De . Biol. 10, 993257. doi:10.3389/ cell.2022.993257 Fagundes, R., and Teixei a, L. K. (2021). Cyclin E/CDK2: DNA eplica ion, eplica ion s ess and genomic ins abili y. F on . Cell De . Biol. 9, 774845. doi:10.3389/ cell.2021.774845 Mache e , M., and Halazone is, T. D. (2015). DNA eplica ion s ess as a hallma k o cance . Annu Re . Pa hol. 10, 425–448. doi:10.1146/annu e -pa hol-012414-040424 Molano-Fe nández, M., Hickson, I. D., and He anz, H. (2023). Cyclin E o e exp ession in he D osophila accesso y gland induces issue dysplasia. F on . Cell De . Biol. 10, 992253. doi:10.3389/ cell.2022.992253 Rambu , A., Viala , M., Beaudoin, C., Lou s-Cale , C., Lobacca o, J. M., Ba on, S., e al. (2021). D osophila accesso y gland: A complemen a y in i o model o b ing new insigh o p os a e cance . Cells 10 (9), 2387. doi:10.3390/cells10092387 Ruiz-Losada, M., Gonzalez, R., Pe opad e, A.,Gil-Gal ez,A.,Tena,J.J.,Baonza,A., e al. (2022). Coo dina ion be ween cell p oli e a ion and apop osis a e DNA damage in D osophila. Cell Dea h Di e . 29 (4), 832–845. doi:10.1038/s41418- 021-00898-6 Saini, N., and Sa in, A. (2020). Nucleola localiza ion o he No ch4 in acellula domain unde pins i s egula ion o he cellula esponse o geno oxic s esso s. Cell Dea h Disco . 6, 7. doi:10.1038/s41420-020-0242-y Saini, N., Bheeshmacha , G., and Sa in, A. (2022). Si uin1 medi a ed modifica ion o No ch1 in acellula domain egula es nucleola localiza ion and ac i a ion o dis inc signaling cascades. F on . Cell De . Biol. 10, 988816. doi:10.3389/ cell.2022.988816 Se as, F. (2022). The soone , he be e : ROS, kinases and nu ien s a he onse o he damage esponse in D osophila. F on . Cell De . Biol. 10, 1047823. doi:10.3389/ cell. 2022.1047823 Ve mezo ic, J., Adamowicz, M., San a pia, L., Rus ighi, A., Fo ca o, M., Lucano, C., e al. (2015). No ch is a di ec nega i e egula o o he DNA-damage esponse. Na . S uc . Mol. Biol. 22, 417–424. doi:10.1038/nsmb.3013 F on ie s in Cell and De elopmen al Biology on ie sin.o g03 Baena-López e al. 10.3389/ cell.2023.1175155