By Jenny Kay, Research Translation Core director and Project 4 Postdoc
Greetings, MIT SRP blog readers!
This month we’re going to discuss why some people are more likely to get cancer than others.
As you’ll recall, cancer generally arises from mutations in the genetic code. Mutations can happen randomly, even in healthy cells, but they become more likely if DNA has been damaged. To prevent DNA damage from causing mutations, every organism has evolved DNA repair mechanisms to fix damage and preserve the genetic sequence. Humans have at least six different DNA repair pathways (depending how you count), each of which is particularly suited to certain types of damage.
Here are (very) simplified descriptions of the major DNA repair pathways and the damage they fix:
- Mismatch Repair (MMR) happens as DNA is being synthesized, such as during replication. If the incorrect nucleotide is incorporated (e.g., A gets added opposite C), the replication machinery backtracks, removes the newly created mismatch, and synthesis resumes.
- Direct Reversal (DR) deals with small chemical additions, called adducts, on nucleotide bases. An enzyme or protein directly removes atoms that shouldn’t be on the base, restoring the original structure.
- Base Excision Repair (BER) also deals with damage to single nucleotides. Rather than removing the lesion on the nucleotide, BER removes the entire base from the DNA strand, and then reads the complementary strand to fill in the gap. BER proteins can also repair breakage of the DNA backbone, provided only one side of the double helix is broken.
- Nucleotide Excision Repair (NER) repairs damage that causes distortion to the DNA double helix. Very large adducts on nucleotides (e.g., benzo[a]pyrene adduct on guanine) and crosslinks between nucleotides cause the helix to contort. The cell identifies the lesion causing the bend, removes a whole segment of that strand (about 30 nucleotides) containing the distorting lesion, and then uses the complementary strand to fill in the gap.
- Non-Homologous End Joining (NHEJ) repairs double strand breaks, where both backbones of the double helix are broken. NHEJ takes the two ends of DNA that were once connected and joins them directly back together.
- Homologous Recombination (HR) also repairs double strand breaks, but only when the cell is preparing to divide. During cell division, when the entire genome has been duplicated for partitioning into the new daughter cells, thereare two identical copies of every chromosome, one for each daughter cell (these duplicate copies are called sister chromatids). A double strand break in one chromatid can be repaired by using the identical sister chromatid to fill in any lost information.
Different types of cells encounter various types of DNA damage to varying degrees, so certain cells and tissues rely more on some DNA repair pathways than others. For example, UV light exposure can cause thymine bases to react and stick together, forming a crosslink that distorts the double helix. Therefore, skin cells rely heavily on NER, and defects in NER increase the likelihood of skin cancer.
In the case of N-nitrosodimethylamine (NDMA), one of MIT SRP’s chemicals of interest, exposure leads to the addition of a carbon and three hydrogens (a “methyl group”, for the chemists out there) to adenine and guanine, producing the structures shown. These little adducts can be disruptive enough to the nucleotide structure that they confuse the cell into incorporating the wrong base, or they block DNA replication altogether.
Importantly, all DNA repair activities are carried out by proteins. Since all proteins are coded in DNA, mutations sometimes occur in the genes that code for DNA repair proteins. If one DNA repair protein becomes mutated, it can cause problems for the entire repair pathway, reducing efficiency and increasing the opportunity for errors. Mutations in DNA repair genes are extremely common in cancer development, at least in part because they facilitate the accumulation of ever more mutations.
Mutations in DNA repair genes can be inherited or arise over time. Inherited deficiencies in DNA repair genes strongly predispose people to developing cancer early in life, since DNA is never properly protected and mutations accumulate more rapidly. For example, inherited mutations in some NER genes cause a 2,000-fold increase in skin cancer susceptibility, and people with these deficiencies must be shielded from all sunlight. Similarly, inherited defects in some HR genes result in vastly increased risk of breast cancer, prompting many women with these mutations to get preventative mastectomies to reduce their cancer risk. There are also nuanced differences in DNA repair capacity among all individuals, as some variants of DNA repair proteins have slightly increased or decreased activity, producing less severe health outcomes.
Aging also facilitates the progressive accumulation of mutations, because every cell division presents the opportunity for new mutations to arise. Taking the skin example, UV-induced DNA damage from sunburns may cause mutations in those skin cells, some of which could occur in NER genes. As we age, those cells continually divide to maintain healthy functional skin, but division of mutant cells leads to entire mutant populations over time. Repeated sunburns compound that effect, both by proliferation of mutant cells and by induction of new mutations. The same logic applies to all dividing cells, which is why aging increases risk for most types of cancer.
Here at the MIT SRP Center, Project 4 is examining how genes involved in repairing NDMA-induced DNA damage impact susceptibility to cancer. Both Direct Reversal and Base Excision Repair are active in fixing NDMA-induced lesions, so the activity of each pathway is likely to impact a person’s susceptibility to NDMA-induced mutations and cancer. To gain some insight about genetic susceptibility, we have animals with “normal” DNA repair activity, animals lacking a major DR protein, animals lacking a major BER protein, and animals with increased BER activity. This will allow us to determine the relative importance of each repair pathway, and also provide insight regarding individuals’ cancer risk based on genetics.
Overall, cancer risk depends on a lot of factors, including the type, timing, and amount of DNA damage (i.e., history of exposure); inherited efficiencies of DNA repair pathways (i.e., genetics); and the random mutations you accumulate over your lifetime (i.e., luck). Since cancer is a product of each of these factors, and you can’t do much about your genetics or luck, I recommend avoiding DNA damage when possible!