Telomeres are defined as specialized nucleoprotein composites that are localised at the terminals of the chromosome. Their construction consists in DNA repetitions: TTAGGG ( in craniates ) , ( d’Adda di Fagagna et Al. 2004 ) . Because of their location, the telomeres have the capacity to shorten the chromosome ends, this holding a protective function for the cistrons located near the terminal of the chromosome by non leting them to degrade.
Telomere viability and construction is maintained by lengthening and shortening dynamic procedures, that consequence in instance of uncomplete DNA reproduction, nucleotide debasement or telomere shortening, ( Longhese, 2008 ) . During cell division the length of the telomeres is controlled by the enzyme called telomerase, which prevents telomere shortening.
In instance of DNA harm, the DNA harm response boots in as a response to the signal sent by the damaged cell, to assist modulate the cell endurance by commanding the cell proliferation.
The DNA harm response is a procedure that consequences in mutants that appear as mistakes during DNA reproduction, chromosomal division or thanks to the environment radiations, chemical or biological agents ( Turnpenny and Ellard, 2005 ) .
The DNA harm response recruits DNA fix proteins to sites of DNA harm to assist decelerating down or to halt the cell rhythm events traveling farther ( d’Adda di Fagagna et al. , 2004 ) .
The DNA harm response is composed by one portion that senses, signals and repairs the Deoxyribonucleic acid harm. This constituent is activated by DNA damaging agents with the intent to reconstruct the damaged DNA sequence. The 2nd constituent of the DNA harm response is the signalling molecules that allow fix in certain checkpoints of the cell rhythm. If the fix is non possible the first 2 events lead to the 3rd 1: programmed cell death. Apoptosis is induced in instance of uneffective repairing ( Slijepcevic, 2006 ) .
Dysfunctional telomeres have been associated with ageing diseases and malignant neoplastic disease. Around 90-95 % of the human malignant neoplastic disease is found to hold unregulated telomerase. Direct cellular factors TRF1, TRF2, and indirect shelterin complex PlnX, Apollo are act uponing the telomeres construction and map ( De Boeck et al. , 2008 ) .
Telomere adhering factor 1
Telomere adhering factor 2
DNA harm factors upregulated
Length shortening, mergers
Poly ( ADP-ribose ) polymerase
End-capping: making T-loops
Breast cancer-associated 1
Regulating transcript hTERT
Table1. A few DNA harm response proteins and their consequence on telomere care ( updated after De Boeck et al. , 2009 ) .
In Table 1. We see that the DNA harm response proteins might impact the telomere care when non working usually and hence prima to chromosomal instability. As the chromosomal stableness is a procedure dependant on telomere care in the event of telomere dysregulation the chromosomes might take to abnormalcies such as mergers. The dysregulation/regulation of the telomeres is maintained by cistrons such as: ATM, RAD54, RAD51D, RAD9, PARP-1, PKcs, BRCA.
In the “ DNA Repair ” paper by Dr. Predrag Slijepcevic, 2006, with the purpose to seek to happen out if the DNA harm response proteins that are located at the telomeres are a portion of an “ integrative ” theoretical account has led to the “ chromosomal fix ” mechanism. It is known that the telomere care mechanism cooperates with DNA harm response. This is due to the fact that are non supposed to be recognised by the system as DNA dual strand interruptions, so someway the DNA harm response must have a signal that makes it cognizant about the telomere care mechanism. If we are taking in idea DNA harm response mechanisms that are implicated in telomere care such as NHEJ, HR, BER, NER and some recent findings that implicate DNA harm response proteins ( see Table1. ) they lead us into the way that telomere care mechanism could be an built-in portion of a much larger system of mechanisms: “ Integrative theoretical account ” . Proteins such as Ku, RAD51D, DNA PKcs, MRN composite have a faulty impact on telomere cresting taking to dysfunctional telomere metamorphosis. 14 proteins have been identified so far that are known to be involved in DNA harm response and telomere care, such as: BRCA1, PARP1, hRAD9 ( Slijepcevic, 2006 ) .
Harmonizing to the “ integrative theoretical account ” the proteins involved in DNA harm response bind to the telomeres sites without triping the DNA harm response mechanism. Nevertheless the telomere dysfuntions are caused by defectous DNA fix proteins that together with DNA harm mechanisms might ensue in genomic instability.
To demo the importance of telomerase in worlds, for illustration in Dyskeratosys congenital, a terrible inherited BM failure syndrome, characterised by unnatural tegument pigmentation, leucoplakia, and subsequently premature ageing and malignant neoplastic disease is caused by deficient DKC1 and TERC cistron. The TERC cistron is involved in the AD DC, that is a subtype of the DC, where patients are heterozygous for TERC cistron. TERC has a really of import function in telomerase therefore it is critical for good telomere care mechanism ( Marrone et al. , 2005 ) .
ATM ( Ataxia Telangiectasia Mutated ) protein senses and responds to DNA dual strand interruptions as an consequence to external agents ( ionising radiation ) and it known to be a checkpoint protein and its effects are associated with ATR protein. Some think that chromatin changes induces ATM phosphorilation and activation, others think that dual strand interruptions lead to ATM activation after they have they have been bounded to the MRN composite ( MRE11-RAD50-NBS1 ) , ( d’Adda di Fagagna et al. , 2004 ) .
PARP1 ( Poly ( ADP-ribose ) polymerase ) has function in DNA fix, as it recognises and binds to DNA strand interruptions. Plants by interacting with dual strand interruptions fix mechanism and DNA-PKcs composite. Along with Ku86 and DNA- PKcs, PARP1 is responsible for telomere care. Dysfunctional PARP1 may ensue in loss of telomere cresting taking to chromosome mergers ( Espejel et al. , 2004 ) .
BRCA1 – chest malignant neoplastic disease susceptibleness cistron is a tumor suppresser cistron that is correlated with the genome unity stableness. Besides linked to DNA fix are the undermentioned tracts: homologous recombination fix ( HRR ) , not homologous terminal connection ( NHEJ ) and nucleotide deletion fix ( NER ) . It is believed that it might besides be involved in telomerase independent tract of telomere care. Normal functional cistron maintains the telomeres unity whereas dysfunctional BRCA1 induces the activation of p53, mutated BRCA1 consequences in chromosomal mergers and surveies done on mouse embryologic cells have shown that dysfunctional BRCA cause telomere loss and mergers ( McPherson et al. , 2006 ) .
DNA – PK composite ( DNA dependant protein kinase ) composed of KU70, Ku80 and DNA – PK catalytic fractional monetary unit ( DNA – PKcs ) has a really of import function in DNA harm fix thru NHEJ fix mechanism. Known to play a function in DNA dual strand fix and recombination, its dysregulation leads to telomere mergers ( Samper et al. , 2000 ) .
hRad9 has an of import function in telomere care as hRAD9 is portion of the HR fix mechanism. Senses DNA harm therefore participates to DNA harm response, mutant hRAD9 used in surveies have revealed chromatin Bridgess in anaphase and chromosomal mergers ( Slijepcevic, 2006 ) .
Depending of the type of DNA harm, DNA harm response tract may take one of the undermentioned fix mechanism: NHEJ – not homologous terminal connection, HR – homologous recombination, BER – base deletion fix, NER – nucleotide deletion fix, MMR – mismatch fix and DSB – Deoxyribonucleic acid dual strand interruptions.
DSB if unrepaired or misrepaired may take to chromosomal instability that is generated during DNA reproduction or after exposure to certain agents such as ionising agents. NHEJ tract recognises DSB, helps in fall ining broken terminals and besides has a important function in processing and ligating DNA ends. There are six NHEJ factors known so far: Ku70, Ku80, the DNA – dependent kinase catalytic fractional monetary unit ( DNA- PKcs ) , Artemis, XRCC4 and DNA Ligase IV. The heterodimer Ku70 and Ku80 binds to DNA terminals to enroll DNA PK-cs. Endonuclease activity of Artemis is activated by phosphorilation by DNA – PKcs, and as a consequence Artemis cleaves DNA hairpins. Ligase IV is recruited by NHEJ ligation activity along with the XRCC4 cofactor. Artemis and Ligase IV are mutated in familial syndromes, besides doing sensitiveness to ionising radiation. A new NHEJ component was late found called Cernunos – XLF that is believed to work in all NHEJ events ( Sekiguchi and Ferguson, 2006 ) .
HR is a conserved component through the development and is normally recruited by DNA dual strand interruptions. Recruits the RAD52 cistron group and allows the damaged Deoxyribonucleic acid to synapse with a homologous Deoxyribonucleic acid templet. Ligation of the two DNA strands is done by DNA crossing overs ensuing two integral DNA molecules ( d’Adda di Fagagna et al. , 2004 ) .
Surveies have shown that telomere disfunction leads to chromosomal instability, this event being associated with high hazard of malignant neoplastic disease. To prolong this information was shown that patients with caput and cervix malignant neoplastic diseases have shorter telomeres in lymph cells. Besides short telomeres show increased hazard of developing malignant neoplastic disease. Although the mechanism that underlies beneath telomere ordinance is unknown, all the findings suggest that the telomeres could be modulating the DNA harm response, that detects the DNA harm and locates it and afterwards uses specific telomere mechanism in order to keep the unity of the telomeres. If the repairing fails, a normal cell exits the cell rhythm and programmed cell death is followed. The chromosomal fix procedure is characterised by the synthesis of telomere repetitions: de novo synthesis ( Wu et al. , 2003 ) .
The Integrative theoretical account is seeking to demo that DNA harm response mechanism and telomere ordinance mechanism are non two independent instruments but that there is merely one wider harm response system and every individual component Acts of the Apostless as a response to a signal sent by another. As a cogent evidence for this theory is that the telomeric protein TRF2 is non ever located in its telomeric environment but travels to sites of DNA breakage after exposure of cells to ionising radiation. The integrative theoretical account is made out of three constituents: harm processing, cell rhythm control and programmed cell death control. These constituents have proteins that are linked at the DNA harm response sites and the telomeric care sites mechanisms. Functional tool term used by dr. Slijepcevic is mentioning to chromosomal fix and as for illustrations we mention the defects in Ku and DNA-PKcs that lead to two phenotypes one for the telomere care and the other taking to DNA harm response mechanism. As a consequence there is a individual tract functional tool that plays more than one function. All these findings show us that a defect within one mechanism affects both the DNA harm response and the telomere care mechanism ( Slijepcevic, 2006 ) .
The findings done by research workers have helped us understanding better the molecular mechanism that underlies beneath DDR, telomeric and chromosomal care.
Mentioned proteins and possibly more to be discovered have shown to hold an of import function on DNA harm response and telomere care mechanism.
Future research should concentrate on the better word picture of the checkpoint proteins and seek to happen out the molecular mechanism that controls the telomerase.
As portion of the integrative theoretical account, we know that telomeric care requires proteins associated with DNA harm response, however there is still to happen out how the telomeres are non recognised as DNA harm, what other proteins are found in DNA harm response at normal and dysfunctional sites.
Further findings will assist scientists to hold a better apprehension on the subject and it will take to being used in clinical tests.