Telomeres are defined as specialised nucleoprotein complexes that are localised at the ends of the chromosome. Their structure consists in DNA repeats: TTAGGG (in vertebrates), (d'Adda di Fagagna et al. 2004). Because of their location, the telomeres have the capacity to shorten the chromosome ends, this having a protective role for the genes located near the end of the chromosome by not allowing them to degrade.
Telomere viability and structure is maintained by lengthening and shortening dynamic processes, that result in case of incomplete DNA replication, nucleotide degradation 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 case of DNA damage, the DNA damage response kicks in as a response to the signal sent by the damaged cell, to help regulate the cell survival by controlling the cell proliferation.
The DNA damage response is a process that results in mutations that appear as errors during DNA replication, chromosomal division or thanks to the environment radiations, chemical or biological agents (Turnpenny and Ellard, 2005).
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The DNA damage response recruits DNA repair proteins to sites of DNA damage to help slowing down or to stop the cell cycle events going further (d'Adda di Fagagna et al., 2004).
The DNA damage response is composed by one part that senses, signals and repairs the DNA damage. This component is activated by DNA damaging agents with the purpose to restore the damaged DNA sequence. The second component of the DNA damage response is the signalling molecules that allow repair in certain checkpoints of the cell cycle. If the repair is not possible the first 2 events lead to the third one: apoptosis. Apoptosis is induced in case of ineffective repairing (Slijepcevic, 2006).
Dysfunctional telomeres have been associated with ageing diseases and cancer. Around 90-95% of the human cancer is found to have unregulated telomerase. Direct cellular factors TRF1, TRF2, and indirect shelterin complex PlnX, Apollo are influencing the telomeres structure and function (De Boeck et al., 2008).
Telomere binding factor 1
Telomere binding factor 2
DNA damage factors upregulated
Length shortening, fusions
End-capping: creating T-loops
Breast cancer-associated 1
Regulating transcript hTERT
Table1. A few DNA damage response proteins and their effect on telomere maintenance (updated after De Boeck et al., 2009).
In Table 1. We see that the DNA damage response proteins might affect the telomere maintenance when not functioning normally and therefore leading to chromosomal instability. As the chromosomal stability is a process dependent on telomere maintenance in the event of telomere dysregulation the chromosomes might lead to abnormalities such as fusions. The dysregulation/regulation of the telomeres is maintained by genes such as: ATM, RAD54, RAD51D, RAD9, PARP-1, PKcs, BRCA.
In the "DNA Repair" paper by Dr. Predrag Slijepcevic, 2006, with the aim to try to find out if the DNA damage response proteins that are located at the telomeres are a part of an "integrative" model has led to the "chromosomal repair" mechanism. It is known that the telomere maintenance mechanism cooperates with DNA damage response. This is due to the fact that are not supposed to be recognised by the system as DNA double strand breaks, so somehow the DNA damage response must receive a signal that makes it aware about the telomere maintenance mechanism. If we are taking in thought DNA damage response mechanisms that are implicated in telomere maintenance such as NHEJ, HR, BER, NER and some recent findings that implicate DNA damage response proteins (see Table1.) they lead us into the direction that telomere maintenance mechanism could be an integral part of a much larger system of mechanisms: "Integrative model". Proteins such as Ku, RAD51D, DNA PKcs, MRN complex have a defective impact on telomere capping leading to dysfunctional telomere metabolism. 14 proteins have been identified so far that are known to be involved in DNA damage response and telomere maintenance, such as: BRCA1, PARP1, hRAD9 (Slijepcevic, 2006).
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According to the "integrative model" the proteins involved in DNA damage response bind to the telomeres sites without activating the DNA damage response mechanism. Nevertheless the telomere dysfuntions are caused by defectous DNA repair proteins that together with DNA damage mechanisms might result in genomic instability.
To show the importance of telomerase in humans, for example in Dyskeratosys congenital, a severe inherited BM failure syndrome, characterised by abnormal skin pigmentation, leucoplakia, and later premature ageing and cancer is caused by deficient DKC1 and TERC gene. The TERC gene is involved in the AD DC, that is a subtype of the DC, where patients are heterozygous for TERC gene. TERC has a very important role in telomerase therefore it is vital for good telomere maintenance mechanism (Marrone et al., 2005).
ATM (Ataxia Telangiectasia Mutated) protein senses and responds to DNA double strand breaks as an effect to external agents (ionizing radiation) and it known to be a checkpoint protein and its effects are associated with ATR protein. Some think that chromatin alterations induces ATM phosphorilation and activation, others think that double strand breaks lead to ATM activation after they have they have been bounded to the MRN complex (MRE11-RAD50-NBS1), (d'Adda di Fagagna et al., 2004).
PARP1 (Poly(ADP-ribose) polymerase) has role in DNA repair, as it recognises and binds to DNA strand breaks. Works by interacting with double strand breaks repair mechanism and DNA-PKcs complex. Along with Ku86 and DNA- PKcs, PARP1 is responsible for telomere maintenance. Dysfunctional PARP1 may result in loss of telomere capping leading to chromosome fusions (Espejel et al., 2004).
BRCA1 - breast cancer susceptibility gene is a tumour suppressor gene that is correlated with the genome integrity stability. Also linked to DNA repair are the following pathways: homologous recombination repair (HRR), non homologous end joining (NHEJ) and nucleotide excision repair (NER). It is believed that it might also be involved in telomerase independent pathway of telomere maintenance. Normal functional gene maintains the telomeres integrity whereas dysfunctional BRCA1 induces the activation of p53, mutated BRCA1 results in chromosomal fusions and studies done on mouse embryonic cells have shown that dysfunctional BRCA cause telomere loss and fusions (McPherson et al., 2006).
DNA - PK complex (DNA dependant protein kinase) composed of KU70, Ku80 and DNA - PK catalytic subunit (DNA - PKcs) has a very important role in DNA damage repair thru NHEJ repair mechanism. Known to play a role in DNA double strand repair and recombination, its dysregulation leads to telomere fusions (Samper et al., 2000).
hRad9 has an important role in telomere maintenance as hRAD9 is part of the HR repair mechanism. Senses DNA damage thus participates to DNA damage response, mutant hRAD9 used in studies have revealed chromatin bridges in anaphase and chromosomal fusions (Slijepcevic, 2006).
Depending of the type of DNA damage, DNA damage response pathway may choose one of the following repair mechanism: NHEJ - non homologous end joining, HR - homologous recombination, BER - base excision repair, NER - nucleotide excision repair, MMR - mismatch repair and DSB - DNA double strand breaks.
DSB if unrepaired or misrepaired may lead to chromosomal instability that is generated during DNA replication or after exposure to certain agents such as ionizing agents. NHEJ pathway recognises DSB, helps in joining broken ends and also has a crucial role in processing and ligating DNA ends. There are six NHEJ factors known so far: Ku70, Ku80, the DNA - dependent kinase catalytic subunit (DNA- PKcs), Artemis, XRCC4 and DNA Ligase IV. The heterodimer Ku70 and Ku80 binds to DNA ends to recruit DNA PK-cs. Endonuclease activity of Artemis is activated by phosphorilation by DNA - PKcs, and as a result Artemis cleaves DNA hairpins. Ligase IV is recruited by NHEJ ligation activity along with the XRCC4 cofactor. Artemis and Ligase IV are mutated in inherited syndromes, also causing sensitivity to ionizing radiation. A new NHEJ element was recently found called Cernunos - XLF that is believed to function in all NHEJ events (Sekiguchi and Ferguson, 2006).
HR is a conserved element through the evolution and is usually recruited by DNA double strand breaks. Recruits the RAD52 gene group and allows the damaged DNA to synapse with a homologous DNA template. Ligation of the two DNA strands is done by DNA crossovers resulting two intact DNA molecules (d'Adda di Fagagna et al., 2004).
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Studies have shown that telomere dysfunction leads to chromosomal instability, this event being associated with high risk of cancer. To sustain this data was shown that patients with head and neck cancers have shorter telomeres in lymphocytes. Also short telomeres show increased risk of developing cancer. Although the mechanism that underlies beneath telomere regulation is unknown, all the findings suggest that the telomeres could be regulating the DNA damage response, that detects the DNA damage and locates it and afterwards uses specific telomere mechanism in order to maintain the integrity of the telomeres. If the repairing fails, a normal cell exits the cell cycle and apoptosis is followed. The chromosomal repair process is characterised by the synthesis of telomere repeats: de novo synthesis (Wu et al., 2003).
The Integrative model is trying to show that DNA damage response mechanism and telomere regulation mechanism are not two independent instruments but that there is just one wider damage response system and every single element acts as a response to a signal sent by another. As a proof for this theory is that the telomeric protein TRF2 is not always located in its telomeric environment but travels to sites of DNA breakage after exposure of cells to ionizing radiation. The integrative model is made out of three components: damage processing, cell cycle control and apoptosis control. These components have proteins that are linked at the DNA damage response sites and the telomeric maintenance sites mechanisms. Functional tool term used by dr. Slijepcevic is referring to chromosomal repair and as for examples we mention the defects in Ku and DNA-PKcs that lead to two phenotypes one for the telomere maintenance and the other leading to DNA damage response mechanism. As a result there is a single pathway functional tool that plays more than one role. All these findings show us that a defect within one mechanism affects both the DNA damage response and the telomere maintenance mechanism (Slijepcevic, 2006).
The findings done by researchers have helped us understanding better the molecular mechanism that underlies beneath DDR, telomeric and chromosomal maintenance.
Mentioned proteins and maybe more to be discovered have shown to have an important role on DNA damage response and telomere maintenance mechanism.
Future research should focus on the better characterisation of the checkpoint proteins and try to find out the molecular mechanism that controls the telomerase.
As part of the integrative model, we know that telomeric maintenance requires proteins associated with DNA damage response, nevertheless there is still to find out how the telomeres are not recognised as DNA damage, what other proteins are found in DNA damage response at normal and dysfunctional sites.
Further findings will help scientists to have a better understanding on the topic and it will lead to being used in clinical trials.