Structural Biochemistry/Nucleic Acid/Biology of Cancer/Defective Repair of DNA

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Many cancers are caused by the defective repair of DNA and by mutations in genes associated with growth control. Defects in DNA-repair systems increase the overall frequency of mutations and, hence, the likelihood of cancer-causing mutations. Indeed, the synergy between studies of mutations that predispose people to cancer and studies of DNA repair in model organisms has been tremendous in revealing the biochemistry of DNA-repair pathways.

A DNA repair mechanism.

Genes for DNA-repair proteins are often tumor-suppressor genes; that is, they suppress tumor development when at least one copy of the gene is free of a deleterious mutation. When both copies of a gene are mutated, however, tumors develop at rates greater than those for the population at large. People who inherit defects in a single tumor-suppressor allele do not necessarily develop cancer but are susceptible to developing the disease because only the one remaining normal copy of the gene must develop a new defect to further the development of cancer.

Cancer cells often have two characteristics that make them especially vulnerable to agents that damage DNA molecules. First, they divide frequently, and so their DNA replication pathways are more active than they are in most cells. Second, cancer cells often have defects in DNA-repair pathways. Several agents widely used in cancer chemotherapy, including cyclophosphamide and cisplatin, act by damaging DNA. However, because chemotherapy drugs are largely non-specific, this results in damage to healthy cells and other side effects.

Disorders[edit]

There are a few human disorders characterized by defects in DNA repair.

1. Xeroderma pigmentosm – the patients with XP have clinical sun sensitivity, a lot of freckle-like lesions due to sun explosion and about 1000-fold increase of developing skin cancer. Several of XP patients have progressive neurologic degeneration. XP cells are very sensitive to UV and have defected DNA repair. The defective genes in XP are involved in nucleotide exclusion repair.

Nucleotide exclusion repair (NER) is a process that is carried out by proteins; these proteins' codes are in the genes, XPA-G, in which are the genes that are affected by mutations that are linked with XP cases. This process (NER) is a method by the cells to get rid of dangerous injuries created in the genetic components by UV rays from the sun. So, for patients with XP, this process does not work correctly. [1]

2. Cockayne syndrome – the patients with this syndrome have sun sensitivity, short stature, and progressive neurologic degeneration. Unlike XP, Cockayne syndrome patients are very sensitive to killing by UV and have defective DNA repair of actively transcribing genes. It also contains two complementation groups. The defective genes also are involved in both nucleotide exclusion and transcription like XP, yet the precise function is unknown.

Roughly half of CS patients will display a changed cellular response to UV rays as a result of mutations in the genes, CSA and CSB. The genes CSA and CSB both code proteins that are related in repairing a particular portion of the DNA that is in current use by the cell.[1]

3. Trichothiodystrophy – the patients with TTD have photosensitivity, short stature, mental and growth retardation and sulphur deficient brittle hair. It does not associate with cancer. TTD patients’ cells are also very sensitive to killing by UV and have defective DNA exclusion repair. The defective genes in TTD are found in one of the XP complementation group.

About half of TTD patients, who display sun sensitivity, have a defect in their nucleotide excision repair. This is a result from mistakes in one of three genes, which are the following: XPB, XPD, and TTDA. With recent findings, there are patients with non-photo-sensitivity, due to a defect in the gene C7orf11(TTDN1). [1]

BRCA1[edit]

BRCA1 is a gene that is involved in DNA repair via homologous recombination. When one allele of this gene is mutated, there is a 85% risk for breast cancer and 30-50% risk for ovarian cancer. BRCA1 produces the BRCA1 tumor suppressor protein, which is made up of 1863 amino acids. This protein can be divided into several domains: RING, exon 11, coiled-coil doman, and BRCT.

RING - This domain consists of the first 150 amino acids of BRCA1. BRCA1 heterodimerizes with BARD1, BRCA1-associated RING domain protein.

Exon 11 - This domain is the middle 60% of the protein.

Coiled-coil domain - This domain is associated with PalB2 and its interactions with BRCA2, another tumor suppressor protein. PalB2 connects BRCA1 and BRCA2 together. It is also active in homologous repair of BRCA1 and BRCA2.

BRCT - This domain interacts with phosphoserine residues on binding partners and facilitates in DNA double-strand breaks localization.

BRCA1 and BRCA 2 are proteins that are closely associated with breast and ovarian cancer. The gene’s main job is to repair any double stranded breaks (DSB) and fight against cancer caused by mutations on the DSBs. BRCA1 and BRCA2 do not work independently to repair the breaks, but have specific jobs and work through a protein network.

BRCA1 acts as a coordinator of all the proteins necessary to repair the break because of its and damage sensing abilities. It first binds to the DSB using RING (Really interesting new gene), which is encoded and forms the BARD1 complex. If the RING part of the BRCA1 protein is mutated or disabled, BRCA1 becomes unable to bind to a DSB and the likelihood of cancer increases.

BRCA1, the coordinator, then recruits PalB2 that in turn attaches BRCA2 to the complex. BRCA2, unlike BRCA1, has a large role in repairing DSBs and is known as an effector that uses Rad51 to help use homologous recombination to repair the DSBs. When the protein complex fails to use homologous recombination, Non-homologous end joining (NHEJ) is used- often leading to further complications.

Ultimately, to best repair DSBs, the BRCA1-PalB2-BRCA2 complex needs to be fully functioning.[2]

References[edit]

  1. a b c [1], DNA-Repair-Disorders.
  2. Links between genome integrity and BRCA1 tumor suppression. Li ML, Greenberg RA. Trends Biochem Sci. 2012 Oct;37(10):418-24. doi: 10.1016/j.tibs.2012.06.007. Epub 2012 Jul 24. PMID: 22836122 [PubMed - in process]