Danny Arroyave Zuluaga

Medicine student

III semester

Molecular biology

“DNA topoisomerases in mtDNA maintenance and

ageing” and “DNA damage checkpoints in nasopharyngeal

carcinoma”

News about the different types

and forms that have studied the

DNA and the greatest influence

on cellular activity. All these

investigations are clear

examples of evolution in the

study of DNA and how it will be

able to prevent many of the

things that today we can only

hope.

INTRODUCTION

DNA topoisomerases in mtDNA maintenance and ageing

ScienceDirect, January, 2014

• Strand separation during transcription and

replication of the closed double stranded

mtDNA form creates topological stress that

interferes with these processes unless that

stress is released in a timely fashion. The

only enzymes capable of performing this

task are topoisomerases. Three

topoisomerases have been found in

mammalian mitochondria

• TOP1MT catalyses the transient cleavage

and ligation of one strand of the DNA double

helix, thereby providing the major activity for

relaxation of mtDNA supercoils.

• TOP3A plays an essential role in nuclear

transcription.

• TOP2B is the only known type II

topoisomerase present in mitochondria,

which is able to catalyse cleavage, passage

and ligation of both strands of the DNA

double helix.

DNA topoisomerases in mtDNA maintenance and ageing

ScienceDirect, January, 2014

• Substances inducing DNA breaks by

inhibiting the ligation step of TOP1 or TOP2

are termed topoisomerase poisons because

they turn the entire tipoisomerase

complement of a cell into a DNA-damaging

agent.

• Interestingly the widely prescribed analgesic

drug Acetaminophen is likewise metabolised

to a 1,4-benzoquinone derivative that

effectively poisons mammalian TOP2 and

possibly triggers liver carcinogenesis in

humans.

• In summary these observations support the

hypothesis that topoisomerase-mediated

DNA-breaks indeed contribute to age-

related mtDNA attrition.

DNA topoisomerases in mtDNA maintenance and ageing

ScienceDirect, January, 2014

• TOP1MT acts as a dominant negative

regulator of mtDNA transcription and this

function requires the enzyme to be active in

terms of relaxation of DNA supercoils.

• It has long been known that TOP1 activity is

liable to attack by thiol-reactive, affecting

transcription.

• An inadequate increase in TOP1mt activity

indeed has the potential to induce

mitochondrial dysfunctions.

• The inadequate TOP1mt activity could also

be due to habitual chronic exposure to

catalytic TOP1 inhibitors such as

naphtoquinones or anthocyanidins possibly

contained in food supplements.

DNA topoisomerases in mtDNA maintenance and ageing

ScienceDirect, January, 2014

• The DNA topoisomerases are as essential

for DNAmt maintenance and function, as

they are for corresponding processes in the

cell nucleus.

• Dysfunction or exogenous disruption of

these enzymes could be involved in chronic

mtDNA attrition.

• Enhanced mtDNA recombination in aged

human myocardium could be due to an

altered balance of helicase and

topoisomerase activity.

• Mutations in three members of this enzymes

family are associated with genome instability

in human progeroid syndromes, like Blooms,

Werners and Rothmund-Thomsons

syndromes.

OBSERVATION

I think that we can

handle these as vital

enzymes in the cell

cycle, we could help

prevent mutations in

DNA, and solve many of

the problematic of today

DNA damage checkpoints in nasopharyngeal carcinoma

ScienceDirect, May, 2014

• The radiotherapy and other

chemotherapeutic agents mainly activate the

DNA damage responses in promoting cell

cycle arrest and apoptosis in NPC cells.

DNA damage checkpoints can therefore be

viewed as a double-edged sword for NPC.

• The checkpoints of the cell cycle is between

G1 and S, G2 and M

• The ATR–CHK1 pathway is essential even

in the absence of exogenous stresses

during unperturbed S phase, probably for

maintaining high rates of replication fork

progression.

DNA damage checkpoints in nasopharyngeal carcinoma

ScienceDirect, May, 2014

• Replication of damaged DNA is prevented

by the intra-S checkpoint. Nevertheless, a

hallmark of the checkpoint is that it slows

down but does not abolish DNA synthesis.

• The S checkpoint affects two distinct

processes: origin firing and the rate of

replication folk progression.

• It is well established that the G1 DNA

damage checkpoint involves the stabilization

and activation of p53.

• The activity of p53 is highly regulated by

post-translational mechanisms including

protein–protein interaction, acetylation,

neddylation, phosphorylation, sumoylation,

and ubiquitination.

DNA damage checkpoints in nasopharyngeal carcinoma

ScienceDirect, May, 2014

• Mounting evidence indicates that the DNA

damage checkpoints in NPC are disrupted

by multiple mechanisms.

• The most of other impairments appear to

target the G1 DNA damage checkpoint.

• Promoter methylation, microRNAs, and

EBV-encoded proteins are some of major

mechanisms involved.

• It should be noted that in addition to NPC,

EBV is associated with a variety of other

human tumors including Burkitt’s lymphoma,

Hodgkin’s disease, lymphoproliferative

disease in immunosuppressed patients,

some T-cell lymphomas, and gastric cancer.

DNA damage checkpoints in nasopharyngeal carcinoma

ScienceDirect, May, 2014

• At least in B cells, EBV infection activates

the DNA damage checkpoint by promoting

the phosphorylation of ATM, CHK2, and the

formation of 53BP1 nuclear foci.

• This DNA damage response is independent

on viral replication, suggesting that it may be

a cellular response to restrict viral-mediated

cellular proliferation.

• Many of these changes appear to be caused

either directly or indirectly by EBV infection.

• Given the extensive alterations of the DNA

damage checkpoints in NPC, the responses

to radiotherapy should differ significantly to

normal cells

OBSERVATION

Is very important to know all these

checkpoints, and even more with the

tracks, as each has different

proteins, which will be able to be

affected me generate some

pathology, but to be aware of these,

you could prevent many disorders.

DNA topoisomerases in mtDNA maintenance and ageing

• As topoisomerases play

an important role, it is

necessary to have them

control, as many agents

have targeted these

important enzymes,

causing errors in DNA,

and they are so

important, we would be

preventing this.

DNA damage checkpoints in nasopharyngeal carcinoma

• Have a good study of

EBV will help us prevent

a certain way, and

actually decrease

nasopharyngeal

carcinoma, as this virus

causes changes in the

checkpoints directly or

indirectly.

DNA damage checkpoints in nasopharyngeal carcinoma

• In this research, we show

very clearly that you have

to study different

populations, as there are

genetic or epigenetic

changes in the pathways

of cell cycle control,

which would explain the

different susceptibility to

us.

DNA damage checkpoints in nasopharyngeal carcinoma

• With this research, we

opened the door, to study

alterations of DNA

checkpoints, and see if

they can be used to

predict the prognosis of

NPC.

BIBLIOGRAPHY

• Martínez S, Lina María. Biología Molecular. 7 ed. Medellín: UPB.

Facultad de Medicina, 2012. P 78-84

• Stefan Sobek, Fritz Bouge . “DNA topoisomerases in mtDNA

maintenance and ageing”. ScienceDirect, (online magazine), 2014,

available online: http://ac.els-cdn.com/S0531556514000126/1-s2.0-

S0531556514000126-main.pdf?_tid=eb533d20-1f04-11e4-90d0-

00000aacb35d&acdnat=1407506851_69f3332cd563c57e17d5ecc1

23f63f91http://www.sciencedaily.com/releases/2014/01/1401141030

13.htm

• Randy Y.C. Poon. “DNA damage checkpoints in nasopharyngeal

carcinoma”. ScienceDirect, (online magazine), 2014, available

online:

http://www.sciencedirect.com.consultaremota.upb.edu.co/science/art

icle/pii/S136883751400013X

THANKS