Passage
Each time a eukaryotic cell replicates its DNA, the telomeres at the ends of each chromosome become slightly shorter. When telomeres reach a critically short length, the cells enter the senescent state, in which cell division ceases (Figure 1) . In humans, conditions such as hypertension, liver disease, and Alzheimer disease have been associated with the decreased telomere length and resulting senescence that occur as part of the normal aging process.
Figure 1Cells that must be able to divide indefinitely (stem cells and germ cells) express an enzyme known as telomerase. Functional telomerase consists of a protein subunit called telomerase reverse transcriptase (TERT) and a noncoding RNA subunit called telomerase RNA (TR) . Using a portion of TR as a template, telomerase extends telomeres by continuously adding the sequence 5′-TTAGGG-3′ to the ends of chromosomes. The complement strand is then filled in by DNA polymerase. Telomere extension allows these cells to avoid senescence.In healthy somatic cells, however, TERT transcription is generally downregulated by the absence of the oncogene c-Myc and the presence of the tumor suppressor protein WT1. When telomerase is suppressed, the resulting critical telomere shortening has been hypothesized to prevent uncontrolled cell proliferation in adult tissues. In cancerous somatic cells, on the other hand, increased telomerase activity is often associated with tumorigenesis. WT1 is frequently absent and c-Myc is frequently overexpressed in these cells, leading to increased TERT expression.In addition to transcriptional control, TERT can be regulated at the post-transcriptional level. The TERT gene consists of 16 exons and 15 introns that can be spliced into more than 20 different isoforms in humans. Only one isoform (the active isoform) is known to extend telomeres. However, the i2 isoform, in which intron 2 is partially included in the mature mRNA (Figure 2) , has been hypothesized to downregulate residual TERT activity in somatic cells.
Figure 2
Adapted from Cifuentes-rojas C, Shippen DE. Telomerase regulation. Mutat Res. 2012;730(1-2) :20-7.
-If the role of the i2 isoform of the TERT gene proposed in the passage is correct, individuals who express the i2 isoform in somatic cells would be expected to have a decreased risk of:

Question

Passage
Each time a eukaryotic cell replicates its DNA, the telomeres at the ends of each chromosome become slightly shorter. When telomeres reach a critically short length, the cells enter the senescent state, in which cell division ceases (Figure 1) . In humans, conditions such as hypertension, liver disease, and Alzheimer disease have been associated with the decreased telomere length and resulting senescence that occur as part of the normal aging process.

Figure 1Cells that must be able to divide indefinitely (stem cells and germ cells) express an enzyme known as telomerase. Functional telomerase consists of a protein subunit called telomerase reverse transcriptase (TERT) and a noncoding RNA subunit called telomerase RNA (TR) . Using a portion of TR as a template, telomerase extends telomeres by continuously adding the sequence 5′-TTAGGG-3′ to the ends of chromosomes. The complement strand is then filled in by DNA polymerase. Telomere extension allows these cells to avoid senescence.In healthy somatic cells, however, TERT transcription is generally downregulated by the absence of the oncogene c-Myc and the presence of the tumor suppressor protein WT1. When telomerase is suppressed, the resulting critical telomere shortening has been hypothesized to prevent uncontrolled cell proliferation in adult tissues. In cancerous somatic cells, on the other hand, increased telomerase activity is often associated with tumorigenesis. WT1 is frequently absent and c-Myc is frequently overexpressed in these cells, leading to increased TERT expression.In addition to transcriptional control, TERT can be regulated at the post-transcriptional level. The TERT gene consists of 16 exons and 15 introns that can be spliced into more than 20 different isoforms in humans. Only one isoform (the active isoform) is known to extend telomeres. However, the i2 isoform, in which intron 2 is partially included in the mature mRNA (Figure 2) , has been hypothesized to downregulate residual TERT activity in somatic cells.

Figure 2
Adapted from Cifuentes-rojas C, Shippen DE. Telomerase regulation. Mutat Res. 2012;730(1-2) :20-7.
-If the role of the i2 isoform of the TERT gene proposed in the passage is correct, individuals who express the i2 isoform in somatic cells would be expected to have a decreased risk of:

Quizplus · Accepted Answer

11ecba2d_0ff8_54a9_a3bf_65284454a27d_MD0008_00 When protein-encoding DNA is first transcribed to RNA, it is in an immature form known as precursor mRNA (pre-mRNA). Pre-mRNA contains both introns and exons and will be spliced into one of several possible mature mRNA forms, known as isoforms. Each isoform contains a subset of the exons in the pre-mRNA, and may also contain portions of introns. Different mRNA isoforms lead to gene products (proteins) with different properties, and are often used to regulate gene activity. For example, splicing pre-mRNA into an inactive isoform dilutes the amount of active isoform present, and the inactive form may compete with the active form for substrate, reducing the overall activity. Such downregulation may be evolutionarily advantageous as it decreases the harmful effects of an overly active gene product. According to the passage, the i2 isoform of the TERT gene contains a portion of intron 2 and is believed to downregulate the active isoform. The passage also states that telomerase activity in somatic cells is associated with tumorigenesis, or the formation of cancerous tumors. Therefore, i2-mediated downregulation of telomerase activity in somatic cells would be expected to reduce the risk of cancer development. (Choices A, C, and D) The passage lists hypertension, Alzheimer disease, and liver disease as conditions associated with decreased telomere length and senescence. Downregulation of telomerase activity by the i2 isoform of TERT would lead to shortened telomeres and senescent cells, and therefore would increase the risk of these conditions. Educational objective: DNA is initially transcribed as precursor mRNA (pre-mRNA), consisting of introns and exons. The pre-mRNA can then be spliced into one of several possible isoforms, each containing multiple exons, and some containing portions of introns. Many inactive isoforms are believed to help regulate the activity of active isoforms.

Passage Each Time a Eukaryotic Cell Replicates Its DNA, the Telomeres