Abstract
Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.
Highlights
Cancer is notorious as it can attack any part of the body, rapidly grow beyond its usual boundaries, invade adjoining tissues, and spread to other organs, resulting in uncontrolled proliferation and eventually death
Several mechanisms, including Telomerase reverse transcriptase (TERT) amplification, epigenetic changes [231], promoter methylation [239], alterations in alternative splicing of TERT pre-mRNA [214,228], chromatin remodeling, increased copy number, disruption of the telomere position effect (TPE) machinery [231], which is stronger with the longer telomere, and telomere shortening may lead to increased TERT transcription by the loss of TPE [240], which can trigger TERT
Stern et al noted that a single nucleotide mutation in the TERT promoter led to the presence of the H3K4me2/3, which were associated with competent chromatin, and recruited the GA Binding Protein Transcription Factor Subunit Alpha (GABPA)/B1 transcription factor that was transcriptionally active in several cancer cell lines [249]
Summary
Cancer is notorious as it can attack any part of the body, rapidly grow beyond its usual boundaries, invade adjoining tissues, and spread to other organs, resulting in uncontrolled proliferation and eventually death. During the cell division cycle, the eukaryotic DNA polymerase is unable to completely replicate the sequences at the chromosomal ends This is because RNA primers attach at the lagging strand during the synthesis of Okazaki fragments, and the resulting shedding RNA leads to telomere shortening [9]. Apart from the shedding RNA and the generation of the 3 overhang by the sequence-specific exonuclease activity to resect back the 5 end of telomeres [15], telomere shortenings can occur, irrespective of cell replication, due to accumulative oxidative stress [16], host age [17], gender [18], sex hormones [19], and lifestyle factors, such as the lack or presence of exercise [20], obesity and weight loss [21], smoking [22], and unhealthy diets [23].
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