DNA Repair Mechanisms

What causes single-strand breaks?

Oxygen radicals, ionizing radiation, chemotherapeutics

What causes single-base damage?

Oxygen radicals, ionizing radiation, chemotherapeutics

What causes bulky lesions and crosslinks?

UV light, polycyclic aromatic hydrocarbons

What causes base mismatch?

replication stress

What causes double-strand breaks?

ionizing radiation, chemotherapeutics

What repair pathway(s) are impacted by single stranded breaks and single base damages?

Base Excision Repair (BER) 

What repair pathway(s) are impacted by bulky lesions and crosslinks?

Nucleotide Excision Repair (NER)

What repair pathway(s) are impacted by base mismatches?

Mismatch Mediated Repair (MMR)

What repair pathway(s) are impacted by double strand breaks?

Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ)

What proteins are involved in the base excision repair pathway (BER)

MUTYH 

OGG1 (PARP 1 / PARP 2) → 

XRCC1 → 
Pol B / PCNA / FEN1 → 
Ligase III

What does BER target?

chemically altered bases

What is the AP site and which pathway is it involved in?

Apurinic/Apyrimidic site where either a purine or pyrimidine base has been removed from the DNA backbone / BER pathway

What proteins are involved in the nucleotide excision repair (NER) in its first pathway?

GC-NER →

XPD, XPC
DDB1/XPE →

ERCC/XPF →

PCNA Pol delta Pol e →

Ligase I

What proteins are involved in the nucleotide excision repair (NER) in its second pathway?

TC-NER →

RNA pol B
CSA, CSB →

ERCC/XPF →

PCNA Pol delta Pol e →

Ligase I

What proteins are involved in the mismatch mediated repair (MMR)?

MSH2/MSH6
MLH1/PMS2 →

EXO1/PCNA/RCF →

Pol delta →

Ligase I, Ligase IV

What proteins are involved in the homologous recombination (HR)?

ATM MRN complex → 

RPA 
BRCA2/FANCD

RAD51, FANCF → 

Pol delta
Pol e → 

Ligase I

What proteins are involved in the non homologous end-joining (NHEJ)?

KU70, KU80 →

DNA PKs 
Artemis 
XRCC4-XLF → 

Pol u → 

Ligase IV

What kind of lesions is NER specifically for?

Helix-distorting lesions

• pyrimidine dimers (UVB)

• bulky adducts (PAHs)

What’s the difference between GC-NER and TC-NER sub pathways in NER?

GC-NER is global genome coupled and recognizes helix distortion while TC-NER is transcription coupled and recognizes transcription problems

What is the inherited disorder associated with NER?

Xeroderma pigmentosum (XP)

• mutation to XP proteins

• hypersensitive to sun (1000x risk for skin cancer)

• all races

What kind of errors to MMR fix?

errors that have escaped editing by polymerases/exonuclease

Which proteins in MMR recognize the error?

MSH2/MSH6, MLH1, and PMS2

• mutations in MSH linked to Lynch Syndrome (germline)

What’s the difference between HR vs. NHEJ?

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

• doesn’t use sister template

• less accurate

• active throughout cell cycle

• DNA-PK, Ku, Artemis

HR uses undamaged DNA template to repair, leading to reconstruction of the original sequence.

• uses sister chromatid for template

• more accurate

• restricted to the S and G2 phases

• ATM, BRCA, RAD proteins

What inherited syndrome is associated with HR? 

ataxia telagiectasia

• mutation in ATM kinase

• sensitivity to xrays

• higher risk for lymphoma