How DNA Repairs Itself (Proofreading, Oncogenes, Tumor Suppressor Genes, Mismatch, Excision Repair)

Summary

This video from Medicosa Perfect Snail explores DNA replication, repair mechanisms, and their links to cancer. It explains key concepts including DNA polymerase, ligase, proofreading, mismatch repair, nucleotide and base excision repair, and how errors in these processes can lead to mutations. The video also contrasts proto-oncogenes with tumor suppressor genes, detailing how their gain or loss of function contributes to cancer development. Using clear analogies and mnemonics, it connects molecular mechanisms to clinical outcomes like hereditary cancers, Xeroderma Pigmentosum, and Fanconi anemia, while highlighting the importance of cell cycle checkpoints and pharmacological interventions. A comprehensive yet digestible guide for understanding DNA integrity and cancer biology.

Takeaways

• 🧬 DNA replication occurs in the S phase of the cell cycle, using each original strand as a template to create complementary daughter strands.
• 🔬 DNA polymerase synthesizes new DNA and possesses proofreading capabilities to correct errors, while DNA ligase joins Okazaki fragments on the lagging strand.
• 📝 The parent DNA strand is more heavily methylated, allowing DNA polymerase to distinguish it from the newly synthesized daughter strand during repair.
• ⚡ Mutation probability is higher in the lagging strand due to DNA ligase lacking proofreading function.
• 🛡️ Mismatch repair mechanisms, involving proteins like MLH1 and MSH2 in eukaryotes, correct errors that escape DNA polymerase proofreading and prevent cancer.
• ☀️ Nucleotide excision repair removes damaged nucleotides such as thymine dimers caused by UV light, involving excision endonuclease, DNA polymerase, and DNA ligase.
• 🔥 Base excision repair corrects smaller DNA damage, such as deamination of cytosine to uracil, using glycosylases, AP endonuclease, DNA polymerase, and DNA ligase.
• 🚦 Proto-oncogenes act as accelerators of the cell cycle, while tumor suppressor genes act as brakes to inhibit uncontrolled cell division.
• -
• 💥 Cancer can develop via gain-of-function mutations in proto-oncogenes (one hit) or loss-of-function mutations in tumor suppressor genes (two hits).
• 🏥 Specific gene defects cause distinct diseases: e.g., RB and p53 mutations lead to retinoblastoma and Li-Fraumeni syndrome, MLH1/MSH2 defects cause hereditary non-polyposis colorectal cancer, and nucleotide excision repair defects cause xeroderma pigmentosum.
• 💊 Chemotherapy and certain antibacterial/antiviral drugs work by inhibiting DNA replication to prevent uncontrolled cell growth or pathogen proliferation.

Q & A

What are the three main components of DNA?

DNA consists of a sugar, a phosphate group, and a nitrogenous base.

What is the difference between a nucleoside and a nucleotide?

A nucleoside is composed of a sugar plus a nitrogenous base, while a nucleotide includes a sugar, a nitrogenous base, and a phosphate group.

What is the role of DNA polymerase during DNA replication?

DNA polymerase synthesizes new DNA strands complementary to the original strands and possesses proofreading ability to correct errors.

Why does the lagging strand have a higher probability of mutations compared to the leading strand?

The lagging strand is synthesized in fragments (Okazaki fragments) and requires DNA ligase to join them, but DNA ligase lacks proofreading capability, increasing the mutation probability.

How does DNA polymerase distinguish between the parent strand and the daughter strand?

DNA polymerase identifies the parent strand by its higher level of methylation, preserving it while correcting errors in the newly synthesized daughter strand.

What is the difference between base excision repair and nucleotide excision repair?

Base excision repair removes a single erroneous nitrogenous base and replaces it, while nucleotide excision repair removes an entire nucleotide and replaces it.

What types of DNA damage do nucleotide excision repair and base excision repair target?

Nucleotide excision repair targets bulky lesions like thymine dimers caused by UV light, while base excision repair fixes small changes such as cytosine deamination to uracil.

What are proto-oncogenes and tumor suppressor genes?

Proto-oncogenes act as accelerators of cell division, promoting growth, whereas tumor suppressor genes act as brakes, inhibiting uncontrolled cell division.

How can proto-oncogenes and tumor suppressor genes lead to cancer?

A single gain-of-function mutation in a proto-oncogene can drive cancer (like an autosomal dominant effect), while loss-of-function mutations in both alleles of a tumor suppressor gene are needed to cause cancer (similar to a recessive effect).

Give examples of important tumor suppressor genes and their associated cancers.

RB (retinoblastoma) and p53 are tumor suppressor genes; loss of RB function can cause retinoblastoma, while loss of p53 function can lead to Li-Fraumeni syndrome, including breast cancer and soft tissue sarcomas.

What is the significance of DNA repair mechanisms in preventing cancer?

DNA repair mechanisms such as mismatch repair, base excision repair, and nucleotide excision repair correct errors in DNA, preventing mutations that could lead to uncontrolled cell division and cancer.

What is the role of DNA methylation in the proofreading process?

DNA methylation marks the parental strand, helping DNA polymerase identify it and correct errors on the newly synthesized daughter strand without altering the original genetic information.

What types of mutations or defects can lead to hereditary non-polyposis colorectal cancer and xeroderma pigmentosum?

Defects in mismatch repair genes (MLH1 and MSH2) can cause hereditary non-polyposis colorectal cancer, while defects in nucleotide excision repair genes (like XPC, XPA) can cause xeroderma pigmentosum.