THE TELOMERE CLOCK FUNCTION IN COLON MUCOSA AND THE REASON WHY BOTH SHORT AND LONG TELOMERES ARE ASSOCIATED WITH COLORECTAL CANCER
Colorectal cancer (CRC) is associated with variable telomere length but the cause for this is unknown. A new theory poses that all DNA is constantly damaged and as a result constantly mutating (doi.org/10.3389/fspas.2022.1067491). The source of constant DNA damage is minimum ionizing particle (MIP) radiation; certain DNA sequences are more prone to radiation damage (doi.org/10.1111/imm.13700).
Hypothesis:
Telomeres consist of mutation-prone sequences that explain a 50-100 nucleotide loss per cell division. The point in time of decreased inhibition of telomerase modulates telomere length of neoplasia.
Methods:
Telomeres were examined for mutation-prone DNA sequence, in particular somatic hypermutation (SHM) hotspots. The tertiary structure of telomeres was examined for a repetitive target of MIP radiation that causes a repetitive decrease by 50-100 nucleotides per cell cycle. The effect over time of colonic mucosa under a constant rate of random somatic DNA mutations on telomere length was investigated.
Results:
Each two “TTAGGG” hexamer repeats of telomeres contain one “GGGTT” SHM hotspot (Fig 1 Left). About 50-100 single-strand 3’ nucleotides of a chromosome telomere end fold back and form a “D-loop-t-loop” (Fig 1 Right). The single-strand SHM hotspot repeat between double-strand DNA of the t-loop and D-loop is extremely unstable and prone to MIP radiation damage sometime during the cell cycle (red arrow); the irreparable break results in predictable shortening of the telomere by 50-100 nucleotides with each cell division.
Under a constant rate of somatic DNA damage, mutations accumulate throughout the chromosome over time (Fig 2). A decrease in inhibition of telomerase activity early in neoplasia development will prevent telomere shortening with each cell division; therefore, neoplasia will have a long sequence of telomere repeats (TR) compared to adjacent normal mucosa (CRC-TRL). On the contrary, if telomerase activity increases late during neoplasia development, then neoplasia will have a short sequence of TR compared to adjacent normal tissue (CRC-TRS). Telomere deletion mutations may result in short telomeres early in neoplasia development.
Conclusions:
A constant rate of MIP radiation-induced mutations affecting a short sequence of single-strand GGGTT SHM hotspots causes cell cycle-dependent 50-100 nucleotide telomere shortening. The regular shortening of telomeres functions as a cell cycle clock reflecting cumulative chromosomal mutations. Therefore, critically short telomer length reflects a greater risk for mutated proteins or CRC and switches deviding cells to replicative senescence or apoptosis. The time point and rate at which telomerase increases during development of neoplasia and any deletion mutations within the SHM hotspot sequence determine whether CRCs have long or short telomeres; in most cases CRCs will have short telomeres.
Fig 1. The mechanism of telomere shortening. Two consecutive “TTAGGG” hexamers contain a “GGGTT” SHM hotspot (purple, left). Polymerases do not start DNA duplication at the end of a chromosome, leaving a gap of 50-100 nucleotides at the 5’ end (“Hexamer repeats (n)”), which is filled in by telomerase in germ cells. In other cells the telomere 3’ single-strand DNA loops back on itself, invades the duplex telomeric repeats and forms a displacement loop (D-loop, left). The large telomere loop (t-loop) is stabilized by shelterin complexes. The damage-prone, single-strand SHM hotspot DNA between double-strand DNA of the t-loop and D-loop is marked by a red arrow.
Fig 2. Three examples of the outcome of constant random mutations in the colon: normal mucosa, CRC with long telomere repeats (TR) and CRC with short TR. At the top, random mutations do not alter the visible, normal colon morphology and TR gradually decrease over time. In the middle, three critical mutations cause a CRC at age 60 and early activation of telomerase results in long TR (CRC-TRL). At the bottom, the same three critical mutations cause a CRC, and an increased cell division rate (top curve) or a TR deletion mutation (bottom curve) result in short TR (CRC-TRS). The red box contains the ratio of TR in CRC over normal tissues: high in CRC-TRL (blue boxes) and low in CRC-TRS (green boxes).
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