Question

How can breakdown in DNA repair play a role in the development of human cancers?

Short answer

Breakdown in DNA repair can lead to mutations, disrupting cell function and promoting uncontrolled cell growth, thus contributing to cancer development.

Step-by-step solution

- Understand DNA Repair

DNA repair is a set of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. These repair mechanisms ensure the maintenance of genetic stability by correcting DNA damage, which can be caused by various internal and external factors.

- DNA Repair Mechanisms

There are several key DNA repair mechanisms, including nucleotide excision repair, base excision repair, homologous recombination repair, and non-homologous end joining. Each mechanism targets specific types of DNA damage and helps maintain genetic integrity.

- Consequences of DNA Repair Failure

When DNA repair mechanisms fail or are impaired, DNA damage can accumulate. This can lead to mutations, which are changes in the DNA sequence. These mutations can disrupt normal cell function and regulation.

- Role in Cancer Development

Accumulated mutations caused by faulty DNA repair can affect oncogenes or tumor suppressor genes, which regulate cell division and growth. If these genes are damaged, it can lead to uncontrolled cell division and the growth of cancerous tumors.

- Types of Cancers

Certain types of cancers, such as breast, ovarian, and colon cancers, have been linked to inheritable defects in specific DNA repair genes (e.g., BRCA1 and BRCA2). Such defects can increase an individual's susceptibility to developing cancer.

Key concepts

DNA repair mechanisms

Cells constantly face challenges that can damage their DNA. Thankfully, they have evolved various DNA repair mechanisms to fix this damage and ensure survival. These mechanisms are essential for the maintenance of genetic information. The main types of DNA repair include:

• **Nucleotide excision repair (NER)**: Corrects bulky DNA lesions caused by UV radiation and chemical exposure.
• **Base excision repair (BER)**: Fixes small, non-helix-distorting base lesions, often the result of oxidation or deamination.
• **Homologous recombination repair (HRR)**: Uses a sister chromatid to repair double-strand breaks accurately.
• **Non-homologous end joining (NHEJ)**: Directly ligates the broken DNA ends without the need for a homologous template, but can be error-prone.

Each of these repair pathways plays a specific and crucial role in maintaining the integrity of the genome.

genetic stability

Genetic stability refers to the preservation of the base sequence of DNA over time. The stability of our genetic material is crucial for preventing diseases and ensuring proper cellular function. It is maintained through:

• **Accurate DNA replication during cell division**.
• **Effective DNA repair mechanisms** to fix any DNA damage promptly.
• **Proper chromosome segregation during cell division**.

When genetic stability is compromised, it can lead to mutations or genomic instability, which can contribute to the development of various diseases, including cancer.

mutations

Mutations are changes in the DNA sequence that can be caused by errors during DNA replication or as a result of DNA damage that has not been properly repaired. There are several types of mutations:

• **Point mutations**: Changes in a single nucleotide base pair, which can either be silent, missense, or nonsense.
• **Insertions or deletions (Indels)**: The addition or loss of nucleotides, which can shift the reading frame of the gene (frameshift mutations).
• **Chromosomal mutations**: Structural changes in the chromosome, such as translocations, duplications, inversions, or deletions.

Accumulation of mutations, especially in genes involved in cell division and growth, can lead to cancer.

oncogenes

Oncogenes are mutated forms of normal genes (proto-oncogenes) that promote cell growth and division. When proto-oncogenes are altered, they become oncogenes and can cause cells to proliferate uncontrollably, leading to cancer. Essential points about oncogenes include:

• **Originate from normal genes**: Proto-oncogenes have crucial roles in normal cell functions such as growth and differentiation.
• **Mutation or overexpression**: Gain-of-function mutations in these genes can make them oncogenic. This can result from point mutations, gene amplifications, or chromosome rearrangements.
• **Examples**: Some well-known oncogenes include **KRAS**, **MYC**, and **BCR-ABL**.

These genes are often the targets of cancer therapies aimed at halting tumor growth.

tumor suppressor genes

Tumor suppressor genes are like the brakes in a car. They regulate cell growth and ensure cells don't divide too quickly or uncontrollably. When these genes are inactivated through mutation or loss, cells can grow out of control. Key points to consider:

• **Function**: These genes control cell cycle checkpoints, promote DNA repair, and can initiate apoptosis (programmed cell death) if damage is irreparable.
• **Two-hit hypothesis**: Typically, both alleles (gene copies) must be inactivated for loss of function (e.g., **p53**).
• **Examples**: Notable tumor suppressor genes include **TP53**, **RB1**, and **BRCA1/BRCA2**.

Loss of these critical genes' function can heavily contribute to the development of various cancers.