DNA Repair, Cancer Development and Synthetic Lethality

This set of vocabulary flashcards covers the mechanisms of DNA repair, the diseases associated with their failure, and the clinical application of synthetic lethality.

DNA repair mechanisms

Highly coordinated systems in cells that detect and repair different forms of DNA damage to preserve genomic integrity and prevent mutation accumulation.

Base excision repair (BER)

A pathway that repairs small base lesions caused by oxidation, alkylation, or deamination using DNA glycosylases and Poly(ADP-ribose) polymerase (PARP).

DNA glycosylases

Enzymes in the Base excision repair (BER) pathway that recognize and remove damaged bases.

Poly(ADP-ribose) polymerase (PARP)

A key enzyme involved in Base excision repair (BER) responsible for repairing single-strand DNA breaks.

Nucleotide excision repair (NER)

A major pathway that repairs bulky DNA lesions, such as thymine dimers produced by ultraviolet radiation, by excising and replacing the damaged strand.

Xeroderma pigmentosum

A disorder characterized by extreme UV sensitivity and increased skin cancer risk, resulting from defects in the Nucleotide excision repair (NER) pathway.

Mismatch repair (MMR)

A system that corrects base mismatches and insertion-deletion loops occurring during DNA replication.

$MLH1$, $MSH2$ and $MSH6$

Specific proteins that are essential components of the mismatch repair (MMR) system.

Microsatellite instability

A condition resulting from the loss of mismatch repair (MMR) function, which lead to increased mutation rates.

Lynch syndrome

An inherited predisposition to colorectal cancer caused by germline mutations in mismatch repair genes.

Homologous recombination (HR)

A high-fidelity DNA double-strand break repair pathway that utilizes a sister chromatid as an accurate template.

$BRCA1$ and $BRCA2$

Critical proteins for homologous recombination (HR) repair; mutations in these increase the risk of breast and ovarian cancer.

Non-homologous end joining (NHEJ)

An error-prone repair pathway that directly ligates broken DNA ends without a template, potentially leading to chromosomal translocations.

Genomic instability

One of the enabling characteristics of cancer that occurs when DNA repair fails, leading to the accumulation of mutations in oncogenes and tumour suppressor genes.

$p53$ mutations

Mutations that prevent cell-cycle arrest and apoptosis following DNA damage, contributing to carcinogenesis.

Synthetic lethality

A therapeutic concept where the simultaneous loss of two repair pathways causes cell death, whereas the loss of either alone is compatible with survival.

PARP inhibitors

Drugs such as olaparib that block single-strand break repair, triggering synthetic lethality in $BRCA$-deficient tumour cells.

Olaparib

A specific example of a PARP inhibitor used in precision medicine to treat cancers with $BRCA1$ or $BRCA2$ mutations.