IMED1004 - Genome Damage, Cancer and Smoking (L28)

Cell Cycle

Note: The Gaps (G1 and G2) are not simply time delays, allow time for cell to monitor internal and external environment

- ensure conditions are suitable and preparations are complete before cell undertakes major processes of S (and M) phase

- G1 is especially important, its length can vary considerably depending on external conditions and extracellular signals

- Therefore if conditions are unfavourable, cells delay their progress through G1 and do not enter S

Overview

- in humans, cell survival and proliferation are highly regulated by integrated controls that continually evaluate the state of the cell and its environment

- normal cell proliferation is modulated by tight and appropriate control of the cell cycle

- apoptosis eliminates damaged cells and cells needed only temporarily during development

- the accumulation of mutations in cancer cells allows them to escape apoptosis and proliferation controls

Apoptosis (Programmed Cell Death)

- in multicellular organisms, systems have evolved to eliminate damaged cells = self destruct mechanisms

- can be activated under many different circumstances e.g cells that are no longer needed for development

4 different types of cells: 3 normal cells and one cancer cell

- first cell is receieivng proper external cues for normal cell survival and proliferation

- second cell is receieivng proper external cues for normal cell death and inhibition of proliferation

- 3rd cell is receieving proper external cues for normal cell survival without proliferation

- 4th cell is self generated survival and proliferation signals in cancer cells

Origins of Mutations

INDUCED:

- presence of mutagen

- mutagens cause mutations - greater dose = more mutations

DIAGRAM ON SLIDE 7 (diagram is for induced)

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SPONTANEOUS:

- absence of mutation

- spontaneous mutations are ultimate source of genetic variation

- Rate is low: 1 cell per 10^5-10^8

- lots of repair mechanisms to keep mutation rate low, but sometimes they fail

Ultraviolet Radiation Damage

One important DNA damage response is triggered by exposure to UV light

- Only UV-A and UV-B radiation able to penetrate earth's atmosphere (depleting ozone layer -> higher levels)

- UV radation -> 2 classes of DNA lesions (pyrimidine dimers and 6-4 photoproducts (6-4PPs)

- Both distort DNA's structure, impeding trasncription and replication

- relatively flexible areas of DNA double helix are most susceptible to damage

- one "hot spot for UV-induced damage is within the p53 gene. p53 protein suppresses tumour formation

Viral Infection: DNA tumour viruses target cell cycle

- Retinoblastoma (Rb) and p53 are tumour suppressor proteins

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Proteins of the Human Papilloma Virus: (dont need to remember thse proteins)

- E7 binds and inhibits Rb

- E6 binds and inhibits p53

- E5 causes sustained activation of a specific growth factor receptor

- sufficient to induce loss of cell cycle control

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- proteins of the large monkey SV40 papova virus "large T" binds and inhibits Rb and p53 (aropund 15% of cancers have osme link to infection)

Lifestyle Choices e.g tobacco smoking

60% of human lung cancers have mutant p53