DNA Repair Mechanisms

One Step Repair

Direct reversal of DNA damage

EX: Chemotherapy

Methylated resides due to alkylating agents

EX: Repair Enzyme

alkyl transferase

MGMT

methyl guanine methyl transferase

Base Excision Repair

single strand break or single base damage

Caused by

radiation, chemo, oxygen radicals

Target

chemically altered bases (single base damage)

Site

apurinic/apyrimidinic site also known as abasic site

scan base pairs for lesions and cleave the base

Glycosylases OGG1 and MUTYH

Endonuclease cleaves the DNA and polymerase

and polymerase replaces the nucleotide and ligase fills gap

what does the PARP interaction with BER proteins do?

Relaxes chromatin for increase DNA accessibility.

Mutations in MUTYH are cause of

MAP syndrome —> germline colon cancer

Nucleotide Excision Repair (NER)

Specific for helix-distorting lesions or Pyrimidine dimers (UVB) and bulky adducts (PAHs).

Lesion is removed by

endonucleases

DNA Polymerase

adds nucleotides

Ligase

seals DNA

Two Sub Pathway

GC-NER

• Global genome coupled

• Recognizes helix distortion

TC-NER

• Transcription coupled

• Recognized transcription problems

Xeroderma pigmentosum (XP)

• Inherited disorder

• Mutation in XP proteins

• Hypersensitive to sun – 1000x risk for skin cancer.

• Can occur in all races

Mismatch Repair (MMR)

Corrects errors that have escaped editing by polymerases/exonuclease

Can also repair

base insertion/deletion that would otherwise cause slippage of strand

Which proteins recognize this error

MSH2/MSH6, MLH1 and PMS2

MMR is removed by

exonuclease, repaired by polymerase, and ligase seals back

Mutations in MMR MSH proteins linked to

Lynch Syndrome

Double Stranded Break Repair

Homologous Recombination (HR)

uses an undamaged DNA template to repair the break, leading to the reconstitution of the original sequence

Uses __ for templates

sister chromatids

How accurate

more accurate

Restricted to which phases

S and G2

Proteins

ATM, BRCA, RAD

Non-Homologous End-Joining (NHEJ)

modifies the broken DNA ends, and ligates them together with no regard for homology, generating deletions or insertions

Does it use the sister template?

no

How accurate

less

When is it active in the cell cycle

throughout the entire cycle

Proteins

DNA-PK, Ku, Artemis proteins

Ataxia telangiectasia

Inherited syndrome
• Mutation in ATM kinase.
• Patients sensitive to X-rays increased
risk of lymphoma

BRCA1/2

Mutations linked to Hereditary Breast and Ovarian Syndrome.
• FANCD proteins include BRCA1/2 and PALB2

Overall Schematic