DNA Repair Mechanisms and Basis of Cancer Genetics

Direct Reversal

photoreactivation, methyl group removal

Single Strand Damage, Base Excision Repair

which
repairs damage to a single base caused by oxidation, alkylation, hydrolysis, or deamination.

1- DNA glycosylases remove damaged base (apurinic or apyrimidinic site).

2- DNA polymerase/ligase

Single Strand Damage, Nucleotide Excision Repair

which recognizes bulky, helix-distorting lesions such as pyrimidine dimers and 6,4 photoproducts.

1-recognition of damage,

2-excision of damaged DNA both upstream and downstream of damage by endonucleases

3- and re-synthesis of removed DNA region

Single Strand Damage, Mismatch Repair

corrects errors of DNA replication and recombination that results in mispaired nucleotides

Double Strand Breaks - non-homologous end joining

pathway that repairs double strand breaks in DNA; the break ends are directly ligated without the need for a homologous template

Double Strand Breaks - microhomology-mediated end joining

use of 5-25 base pair micro homologous sequences during the alignment of broken ends before joining; this results in deletions flanking the original break

Double Strand Breaks - homologous recombination

requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break

• chromosomal crossover during meiosis

• sister chromatid or a homologous chromosome as a template

Cancer cells evade normal growth by…

• produce cell division signals (autocrine stimulation)

• lose contact inhibition

• avoid programmed cell death

Hayflick Limit

the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length

Cancer cells interact with the body…

produce substances that encourage blood vessel growth

• provide nutrients to tumor

• move to other locations

Apoptosis

genetically programmed cell death

• essential for normal embryonic development

• removes abnormal cells from the body

• depends on numerous signals, both inside and outside of the cell

Knudson’s Multistep Model of Cancer

• cancer is the result of a multistep process that requires several mutations

• if one or more mutations are inherited, fewer mutations are required to produce cancer

Proto-oncogenes

• In normal cells

  • Code for proteins involved in the stimulus of cell division

• If altered, may form oncogenes

  • Alone, do not cause malignant cancer

  • Require other mutations, including one in a tumor suppressor gene

• Mutation in oncogenes/tumor suppressor genes cause
  cancer

• Mutation DNA repair genes

Oncogenes act in a…

dominant fashion to promote cancer

nonmutant allele is a…

protooncogene

protooncogenes encode…

proteins needed for cell cycle progression

gain of function mutation

results in increased proliferation

Ras - oncogene (signaling section)

• usually active when bound to growth factor

• oncogenic point mutation makes constitutively active protei

c-Abl - oncogene

• Chromosomal translocation fuses the c-abl and bcr genes

• Hybrid protein encodes a constitutively active tyrosine kinase

Her2 - oncogene

• Found in 20% of all breast cancers

• overexpressed growth factor receptor

Philadelphia Chromosome

• chromosome 22 of leukemia cancer cells

• contains a fusion gene called BCR-ABL1

Tumor Suppressors act…

recessively to promote cancer

Normal alleles of tumor suppressor genes…

encode proteins that slow down the cell cycle

Loss of function mutations…

in both gene copies results in increased proliferation

Rb (tumor suppressor)

normal protein delays entry into S-phase

p53 (tumor suppressor)

normal protein functions in G1/S checkpoint

HNPCC (tumor suppressor)

• Hereditary nonpolyposis colon cancer

• Caused by mutation in any of DNA mismatch repair genes

Haploinsufficiency

• A single functional copy of a gene (with the other copy inactivated by mutation) does not produce enough gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state.

• Retention of a single functional retinoblastoma susceptibility (RB1) allele is insufficient to maintain genome stability.

• Haploinsufficiency of RB1accelerates cancer pathogenesis in concert with inactivation of tumor protein p53

Growth Factors

Extracellular hormones or cell-bound signals that stimulate or
inhibit cell proliferation

Receptors

Comprised of a signal-binding site outside the cell, a transmembrane segment, and an intracellular domain

Signal Transducers

located in cytoplasm

Transcription factors

activate expression of specific genes to either promote or inhibit cell proliferation

Genes that control the cycle of cell division

cyclin-dependent kinases (CDKs)

G1/S transition

Retinoblastoma protein (RB)

G2/M Transition

mitosis promoting factor (MPF)

Flowchart of Genes that Control the Cycle of Cell Division

Different CDK-cyclin complexes govern different cell cycle transitions

Presence of each type depends on:

• synthesis of specific cyclins at certain times

• destruction of cyclins that are not needed

Signal Transduction pathways

external signal triggers a cascade of intracellular reactions producing a specific response

Environmental Risk Factors

Cancer cells can be over-methylated which means that…

hypermethylated

silences the expression of tumor

suppressor genes

Cancer cells can also be under-methylated

hypomethylated

may cause chromosome instability