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Lecture 12

BMS 860 Lecture 12: Cancer Notes 12

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Ryerson University
Biomedical Sciences
BMS 860

Lecture 12: Maintenance of Genomic Integrity and the Development of Cancer Multiple additional genetic and epigenetic changes are required for full malignant transformation of normal cells. Tumor Suppressor Genes: Gatekeepers and Caretakers • gate keepers: o encode proteins that directly inhibit cell proliferation and survival o the loss of gatekeepers directly opens the gates to tumour formation o Examples: Rb, p53 and SMAD4 • caretakers o encode proteins that are involved in DNA repair and the maintenance of chromosome integrity o the loss of caretakers indirectly affects tumour formation by permitting an increased mutation rate for all genes. o BRCA1, BRCA2, APC and ATM • the more the tumor progresses, the easier it is for mutations to occur Genetic instability is caused by the loss of caretakers • Cancer cells accumulate mutations at rates that can be hundreds or even thousands of times higher than normal = genetic instability • Elevated mutation rates increase the probability that occasional mutations will arise and allow cells to escape from normal constraints on cell proliferation and survival. • Elevated mutation rates facilitate tumour progression and cells acquire additional traits – faster growth rate, increased invasiveness, ability to survive in the bloodstream, resistance to immune attack, ability to grow in other organs, resistance to drugs, evasion of apoptosis • Genetic instability occurs in several different forms that differ in their underlying mechanisms: o Telomere attrition leading to aneuploidy o Defects in the DNA repair mechanisms leading to DNA damage ▪ Excision repair, mismatch repair, double-strand DNA breaks repair DNA damage and DNA repair • DNA damage can be caused by: o Endogenous factors (internal sources) ▪ Errors made during DNA replication (DNA polymerase errors) ▪ Errors from endogenous biochemical processes o Exogenous factors (external sources) ▪ Errors made by mutagens • DNA repair mechanisms: o Single strand (SS) repair mechanisms ▪ Nucleotide excision repair ▪ Base excision repair ▪ Mismatch repair o Double strand (DS) repair mechanisms ▪ Non-homologous end joining ▪ Microhomology–mediated end joining ▪ Homologous recombination DNA polymerase and mismatch repair • DNA polymerase occasionally stutters or skips a base when copying a repeated sequence of DNA in the template strand. As a consequence, the newly synthesized strand (green), either may acquire an extra base that increases the length of the repeating sequence or may lack a base. • There are sequences in genes that have highly repeated sequences- if there are more than 100 = satellite, or less than 100 = microsatellite o di-satellite = double repeats • Mismatch repair proteins (MMR) recognize and repair these mistakes made by DNA polymerases, including misincorporated bases and inaccurate replication of microsattelite sequences. • ex. MutS/MutL bacterial homolog MMR protein- Mut S is seen binding to a DNA fragment into which a mismatch has been introduced at a specific nucleotide site. MutS kinks the DNA double helix as it scans for and ultimately finds regions of mismatch where it binds in a stable fashion, removes the strand and repairs DNA synthesis Defects in mismatch repair (MMR) lead to microsatellite instability • Microsatellites = highly repeated short sequences in the genome. • Defects in MMR lead to expansion or shrinkage of microsatellite sequence • Defects in mismatch repair are responsible for the accumulation of a variety of mutations in the genome including incorporation of an inappropriate base in DNA sequence and also an expansion or contraction of the size of a microsatellite repeat sequence • ex. Woman suffering from hereditary form of colon cancer and presenting in the clinic with both a colorectal and a breast carcinoma. This is PCR analysis of BAT25 sequence containing microsattelite sequence. This analysis reveals a clear increase in size of the microsatellite repeat in the colon carcinoma, white the breast tumour exhibits a microsatellite repeat that is precisely the same as normal, control DNA. This suggests that the breast carcinoma, unlike the colon carcinoma, is unlikely to have been caused by MIN. Inherited defects in MMR: Hereditary non-polyposis colon cancer (HNPCC) • Familial cancer syndrome responsible for 2-3% of all colon cancer cases • 80% life time risk of developing colon carcinomas • Germline mutations in the genes encoding MSH2 and MLH1 mismatch repair proteins • Microsatelite instability caused by MMR mutations can affect TGF-b receptor in some HNPCC cases • loss of 2 adenines can cause premature stop codon and protein will be truncated, degraded and inactivated • 15% of sporadic gastric, colorectal, and endometrial tumours have defective MMR Endogenous DNA damage by depurination • Loss of the base adenine or guanine caused by hydrolysis of the bond linking it to the DNA chain • Spontaneous reaction, bond very susceptible to being broken • DNA of a human cell may lose thousands of adenines and guanines every day • In cells, one of the main causes of depurination is the presence of endogenous metabolites undergoing chemical reactions. Endogenous DNA damage by deamination • Removal of an amino group (-NH2) by hydrolysis • Affects bases C, A, and G alters the base-pairing properties of the affected bases • Caused by random collision of a water molecule with the bond that attaches the amino group to the base • In a human cell, rate of DNA damage by deamination is approximately 100 deaminations per day Endogenous DNA damage by oxidation of bases •
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