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
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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 .
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Molano-Fe nández, M., Hickson, I. D., and He anz, H. (2023). Cyclin E
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